Вы находитесь на странице: 1из 92

Republic of the Philippines

Department of Health

September 29, 1999

No. 43 S. 1999







The Bureau of Food and Drugs hereby adopts the 1st edition of Current Good Manufacturing
Practice Guidelines and the specific GMP guidelines hereunder prescribed.


Section 1


This order is issued under the authority conferred upon the Secretary of Health by virtue of
section 26(a) of RA 3720 as amended.
Section 2

Statement of Policies

Drugs shall be manufactured using methods, facilities and control procedures

adequate to preserve their identity, strength, quality and purity.


License to manufacture drugs shall be issued only upon compliance with

Current Good Manufacturing Practice guidelines.


Overall control is essential to ensure the manufacture of drugs conforming

officially recognized standards of quality, efficacy and safety.


The qualities of drug products depend on the starting materials, production,

quality control processes, building, equipment, and personnel involved and
testing protocols.

Section 3

Statement of Objectives

This 1999 GMP guidelines is adopted to:


Prescribe standard guidelines in the manufacture of drug products


Ensure that no person or establishment shall manufacture drugs under

substandard conditions.

Page 1 of 92

Section 4

Definition of Terms

For the purpose of these guidelines, the following terms shall mean:


The nearest value obtained during measurement or analysis to the true value.


Actual Yield
The quantity that is actually produced at any phase of production of a particular
drug product based on the initial input.


An enclosed space with two or more doors, which is interposed between two or
more rooms e.g. of different standard of cleanliness for the purpose of
controlling the air flow between those rooms when they need to be entered. An
airlock may be designed for and used by either people or materials; in the latter
case it can be termed a pass through hatch. An airlock can also be the
anteroom to a clean room in which sterile goods are handled.


Approved Supplier
A supplier of all components of finished products generally approved for use by
the trade and accredited by the manufacturer based on a vendor rating which
include but not limited to conformance to the company or compendium material


A quantity of drug product/device that is homogenous in character and quality
produced during a given cycle of manufacture and from a specific
manufacturing order.


Batch Number
A designation in numbers or letters or combination thereof that identifies the
batch, and permits the tracing of the complete history of a batch, including all
stages of its production, control and distribution.


A contained system, such as a fermenter, into which biological agents are
introduced together with other materials in order to effect their multiplication or
their production of other substances by reaction with other materials.
Biogenerators are generally equipped with devices for regulation, control
connection, material addition and material withdrawal.


Microbiological Agents
Microbiological Agents including genetically engineered microorganisms, cell
cultures, as well as endoparasites, whether pathogenic or not.

Page 2 of 92


Whole blood collected from a single donor and processed either for transfusion
or further manufacturing.

4.10 Bulk Product

Any processed material which has to undergo another process including
packaging operation to become a finished product.

4.11 Calibration

The operations carried out to determine the accuracy of measuring instruments,

of material measures such as masses or gauges and of measurement

4.12 Cell Bank System

A system whereby successive batches of a product manufactured by culture in
cells derived from the same master cell bank (see Master Cell Bank). The cell
bank system is validated for a passage level or number of population doubling
beyond that which was achieved during routine production.

4.13 Cell Culture

The in-vitro growing of cells isolated from multicellular organisms.

4.14 Clean Area

An area with defined environmental control of particulate and microbial
contamination, constructed and used in such a way as to minimize the
introduction, generation and retention of contaminants within the area.

4.15 Compatibility Testing

The in-vitro serological tests performed on donor and recipient blood samples to
establish the serological matching of a donors blood or blood components with
that of a potential recipient.

4.16 Component
Any material intended to be used for the manufacture of a product whether raw
or packaging materials.

4.17 Contained Area

An area constructed, operated and equipped with air-handling and filtration
system in order to prevent contamination of the external environment by
biological agents from within the area.

Page 3 of 92

4.18 Contaminants
Anything that cause contamination to the product.

4.19 Controlled Area

An area constructed and operated to control the introduction of potential
contamination (an air supply approximately class III may be appropriate), and
the consequences of accidental release of living organisms. The level of control
exercise shall reflect the nature of the organism employed in the process. The
area shall be maintained at a pressure negative to the immediate external
environment and allow for the efficient removal of small quantities of airborne

4.20 Cross Contamination

Contaminations of a starting, intermediate product or finished product.

4.21 Cryogenic Vessel

A container designed to store liquefied gas at extremely low temperature.

4.22 Cylinder
A container designed to store gas at a high pressure.

4.23 Date of Manufacture

The date indicating the start of processing of every batch.

4.24 Dispensing
The activity of weighing, counting or measuring and checking of starting
materials and issuing these to the appropriate production personnel; details of
the activity being duly and properly documented.

4.25 Documentation
Written recording of all procedures, instructions and processes involved in the
manufacture of drug products.

4.26 Drug Product

Any substance or mixture of substances in finished dosage forms that is
manufactured, offered for sale, or presented for use in (1) the treatment,
mitigation, cure, prevention, or diagnosis of disease, abnormal physical state, or
the symptoms thereof in man or animal; or (2) the restoration, correction or
modification of organic functions in man or animal; regardless of whether it is in
package form.

Page 4 of 92

4.27 Device
Instrument, apparatus, or contrivances, including their components, parts and
accessories, intended (1) for use in the diagnosis, cure, mitigation, or
prevention of disease in man and animals; or (2) to affect the structure or any
function of the body of man or animal.

4.28 Expiration Date

A date fixed for each individual batch on or before which the batch is expected
to meet the standard specifications for quality, safety and efficacy.

4.29 Facilities
For Blood Products: Any area used for the collection, processing, compatibility
testing, storage or distribution of blood and blood components.
For Other Products (drugs, medical devices, bulk chemical material and
others): This refers to the building, premises and equipment necessary in the
manufacture of drugs.

4.30 Finished Product

A product which has undergone all stages of manufacturing operations.

4.31 Good Manufacturing Practice (GMP)

It is the system of quality assurance aimed at ensuring that products are
consistently manufactured to a quality appropriate for their intended use. It is
thus concerned with both manufacturing and quality control processes and

4.32 Infected ( Man or Animal )

Contaminated with extraneous biological agents and therefore capable of
spreading infection.

4.33 In-Process Control

Checks and tests instituted and carried out in the course of the manufacture of
a drug to assure identity, strength, quality and purity.

4.34 Intermediate Product

Any processed substance or mixture of substances which has to undergo one
or more further stages of processing to become finished product.

4.35 Leukopheresis
The process in which blood is extracted from the donor, a leukocyte concentrate
is separated, and the remaining formed elements and residual plasma are
returned to the donor.

Page 5 of 92

4.36 Liquefied Gases

Gases that, at the specified temperature and pressure, remain as a liquid in the

4.37 Lot
A batch or any portion of batch produced by a continuos process, an amount of
drugs produced in a unit of time or quantity in a manner that assures its
uniformity and in either case which is identified by a distinctive lot number and
has uniform character and quality within specified limits.

4.38 Lot Number

See batch number

4.39 Manifold
Equipment or apparatus designed to enable one or more gas containers to be
filled simultaneously from the same source.

4.40 Manufacture or Manufacturing

The complete set of activities to produce a drug that comprise production and
quality control from dispensing of materials to the release for distribution of the
finished product.

4.41 Master Cell Bank

A culture of fully characterized cells filled into containers in a single operation,
processed together and stored to ensure uniformity and stability. A master cell
bank is normally stored at -70oC or lower.

4.42 Master Seed Lot

A culture of a microorganism distributed from a single bulk into containers in a
single operation to ensure uniformity, stability and to prevent contamination.

4.43 Packaging
The process of packing which is that part of the production cycle applied to a
bulk product to obtain the finished product.

4.44 Packaging Material

Any material used in the packaging of a bulk product to obtain the finished

4.45 Plasma (for further manufacture)

The liquid portion of blood separated and used as material to prepare another

Page 6 of 92

4.46 Plasmapheresis
The process in which blood is extracted from the donor, the plasma is
separated from the formed elements and at least the red blood cells are
returned to the donor.

4.47 Plateletpheresis
The process in which blood is extracted from the donor, the platelet concentrate
is separated, and the remaining formed elements and residual plasma are
returned to the donor.

4.48 Precision ( in analytical assay and method)

The degree of variation between individual test results when the method is used
separately to different samples drawn from the same batch of material. This will
include variation between analysts, between days, between tests on the same
prepared extract of a given sample, between different extracts and between
laboratories conducting the same test. It is normally divided into two types:
- Repeatability (within laboratory), and
- Reproducibility (between laboratories).

4.49 Primary Containment

A system of containment that prevents the dispersal of a biological agent into
the immediate working environment. It involves the employment of closed
containers or safety biological cabinets accompanied with secure operating

4.50 Procedures
Description of the operations to be executed, the precautions to be implemented
directly or indirectly related to the manufacture of a drug.

4.51 Processing
The part of production cycle starting from weighing of raw materials to finished

4.52 Processing of Blood

Any process employed after collection and before computability testing of blood.
It includes the identification of a unit of donor blood, the preparation of
components from such unit of donor blood, serological testing, labeling and
associated record keeping.

4.53 Production
All operations starting from dispensing of materials to processing, packaging, to
finished product.

Page 7 of 92

4.54 Quality Control

All control measures taken designed to ensure that finished products
consistently conform to established specification of identity, strength, purity and

4.55 Quarantine
An act of holding off a material for use, or a product for packaging or distribution
by physically setting it apart or by system duly validated, pending a decision on
release or rejection.

4.56 Raw Material

All substances whether active or excipients that are employed in the processing
of a finished product.

4.57 Reconciliation
A resolution between the theoretical and actual yield.

4.58 Recovery
The incorporation of all or part of previous batches with the required quality into
another batch at a defined step of production.

4.59 Rejected
The status of materials or products which are not permitted to be used for
processing, packaging or distribution.

4.60 Released or Passed

The status of materials or products which are permitted to be used for
processing, packaging or distribution.

4.61 Representative Sample

A sample representing the lot, the batch, or the total amount of materials based
on a sampling plan.

4.62 Reprocessing
The reworking of all or part of a batch of product of an unacceptable quality
from a defined step of production in order that its quality may be rendered
acceptable by one or more additional operations.

4.63 Returned Product

Any finished product which is already in distribution and sent back to the
manufacturer or distributor due to complaint, damage, expiration, validity or

Page 8 of 92

other reasons such as the condition of the container or package which may cast
doubt on the product identity, quality, strength and safety.

4.64 Sanitation
All measures taken to assure suitable or adequate environmental conditions in
compliance to GMP.

4.65 Secondary Containment

Secondary containment is a system of containment that prevents the dispersal
of a biological agent into the external environment or into other working areas. It
involves the use of rooms with specially designed air handling, the existence of
air locks and/or sterilizers for the exit of material. It may add to the effectiveness
of primary containment (see Primary Containment).

4.66 Seed Lot System

A seed lot system is a system where successive batches of product are derived
from the same master seed lot at a given passage level.

4.67 Specification of Material

A description of starting material, intermediate, bulk or finished product in terms
of its chemical, physical and microbiological characteristics, if any. A
specification shall include descriptive and or numerical clauses stating
standards and tolerated deviations, whenever applicable.

4.68 Starting Materials

Raw materials used in the production of a finished product (drugs).

4.69 Sterile Room or Sterile Area

A room or area of defined environmental condition with controlled particulate
and microbial contamination, constructed, equipped and used to eliminate the
introduction, generation or retention of contaminants.

4.70 Sterilization
Inactivation or reduction to an acceptable level of all viable microorganisms by a
suitable process.

4.71 Theoretical Yield

The quantity that is expected or planned to be obtained at any phase of
production of a particular product, based on the quantity of components to be

Page 9 of 92

4.72 Unit (of Blood)

The volume of blood or one of its components in a suitable volume of
anticoagulant obtained from a single collection of blood.

4.73 Validation
The process of confirming by recognized appropriate means or manner, that
any material, process, procedure, activity, system, equipment or mechanics
used in production and control consistently achieved the desired results.

4.74 Working Cell Bank

A culture of cell derived from the master cell bank and intended for use in the
preparation of production of cell cultures and normally stored at - 70OC or

4.75 Working Seed Lot

A culture of microorganism derived from the master seed lot and intended for
use in production.

4.76 Worst Case

A condition or set of conditions encompassing upper and lower processing
limits and circumstances, within standard operating procedures, which pose the
greatest chance of product or process failure when, compared to ideal
conditions. Such conditions do not necessarily induce product or process


Section 1


There shall be an adequate number of personnel at all levels having knowledge, skills and
capabilities relevant to their assigned functions, in good mental and physical health to be able to
execute their duties.


Organization, Qualification and Responsibilities


The organizational structure of the company shall be such that the

production and the quality assurance are headed by different
managers, neither of whom shall be responsible to the other. Each
shall be given full authority and facilities necessary to execute his/her
duties effectively. Neither shall have any interests outside the
manufacturers organization that prevent or restrict their dedication to
the assigned responsibilities or which may be considered to entail a
conflict of interest.


The production manager shall be a PRC registered qualified

pharmacist or any other related profession. He/she shall be
adequately trained and shall posses good practical experience in the

Page 10 of 92

field of pharmaceutical manufacture and managerial skill, which

enable him/her to perform his/her function effectively. The production
manager shall have full authority and responsibility to manage
production of drug products.



The quality control manager shall be a PRC registered qualified

pharmacist or any other related profession. He/she shall have
adequate training and practical experience that will enable him/her to
perform his/her function effectively. The quality assurance manager
shall have full authority and responsibility in all quality control
processes such as establishment, verification and implementation of
all quality control procedures. He/she shall have the sole authority to
approve starting materials, intermediates, bulk and finished products
that meet the specification or to reject those which do not conform to
the relevant specification or which are not manufactured in accordance
with the approved procedures.


The quality assurance manager shall clearly define the field of work
and the method of delegating responsibilities in his/her absence.


The quality assurance manager shall have personal and professional

responsibility for ensuring that various checks and tests have been
carried out. The details of this work may be delegated to an
appropriately trained and experienced staff who would endorse their
work. Finally, the quality assurance manager has to be satisfied
directly by the proper operation of quality systems that include
appropriate approvals, audits, self-inspections and spot checks that
the production and testing have complied with relevant requirements.


The production manager and the quality assurance manager are

jointly responsible to establish for the quality, strength, purity and
efficacy of the finished products.


To support and assist the key personnel, an adequate number of

qualified personnel should be available in the production and quality
assurance. Each personnel shall be adequately trained with their
respective assignment.


The duties and responsibilities of all employees shall be clearly

defined, well understood and shall be within his/her capacity to
perform to ensure quality products.



All employees who are directly and indirectly engaged in the

manufacturing activities shall be trained in the particular operations
that the employees perform in accordance with the principles of
Current Good Manufacturing Practice.


Training shall be conducted by qualified individuals. Special attention

shall be given to training of personnel working in sterile and clean
areas or with highly potent, toxic or sensitizing materials.

Page 11 of 92

Section 2


Training in Current Good Manufacturing Practice shall be on a

continuing basis and with adequate frequency to assure that
employees remain familiar with the Current Good Manufacturing
Practice requirements relevant to their functions.


Training in Current Good Manufacturing Practice shall be in

accordance with written program approved by the production manager
and the quality assurance manager.


Records of personnel training in Current Good Manufacturing Practice

shall be maintained and the effectiveness of training programs shall be
assessed periodically.


After training, the consequential employees performance shall be

appraised to determine their capability to meet the qualification
requirement for the jobs.


The premises for manufacturing shall be of suitable size, design, construction and location to
facilitate proper operation, cleaning and maintenance. The individual working areas shall be
adequate so that any risk of confusion, cross-contamination and other mistakes that will
adversely affect the quality of drugs and devices will be avoided.


Location, Construction, Design & Lay-out


Premises shall be so located and protected against contamination

from the environment.


Premises shall be constructed and maintained to protect against

weather, flood, ground seepage and the access and harboring of
vermin, rodents, birds, insects or other animals.


In determining the design and lay-out of premises, consideration

should be paid to:

the compatibility of other manufacturing operations that

may be carried out in the same or adjacent premises

allow the production to take place in areas connected in a

logical order according to the sequence of the operations
and to the requisite cleanliness levels

the adequacy of the working space, which shall allow

orderly and logical placement of equipment and materials
to suit the operation, efficient flow of work, effective
communication and supervision to avoid crowding and

avoid the use of production areas as a general traffic for

personnel or materials or for storage other than the
materials in process.

Page 12 of 92


The layout of rooms, corridors, and spaces shall provide for logical
movements of materials and personnel with minimal traffic for
operations to be carried out in defined areas and to avoid cross
contamination. The design and layout of premises shall fulfill the
following requirements:

the risk of mix-up between different drugs or their

components, the possibility of cross-contamination by
other drugs or substances and the risk of omission of
any production step shall be prevented

penicillins shall be produced only in separate buildings,

with separate air handling facilities dedicated to these
products using dedicated equipment, including dedicated
packaging lines.

cephalosporins shall be produced in separate buildings,

with separate air handling facilities dedicated to these
products using dedicated equipment, including dedicated
packaging lines

cross contamination of products by live biologicals, or by

drug products, such as certain steroids or cytotoxic
agents which in trace amounts may produce
physiological effects should be prevented by the
following methods: carrying

out production operations in

separate buildings or adequately isolating the
operations by total enclosure or by making
successive batches in the same or in
dedicated equipment followed by validated
cleaning procedures and where appropriate,
fumigation controlling airborne contaminants by the use

of an appropriate air pressure differential in
processing areas and adequate exhaust
systems and filters, together with control of
recirculated air the setting and shielding of production

equipment, and wherever possible, the use
of equipment solely for one type of
drug/product; containment

of contaminant-transfer by
means of airlocks, clothing change and
decontamination of containers and other
articles prior to their removal from the
isolated area separate cleaning area for contaminated


Page 13 of 92 periodic testing of the environment around

the production areas for the presence of the
therapeutic substance being processed and validation of cleaning procedures.


In all manufacturing rooms (processing and packaging), air supply and

air exhaust points shall not be so close or so disposed as to restrict or
negate the supply of clean air to worksites and or movement of
product dust or other contaminants away from worksites. The airflow
pattern within the facility and each manufacturing area and the
throughput rate of air shall be selected to afford adequate protection to
the products and personnel.
A plan of the building(s) showing air handling facilities including key air
handling equipment and showing air quality standards, flow rates,
proportions re-circulated and relative air pressures shall be made
available for inspection.


Air handling facilities for the production of cytotoxins shall be

appropriate. The anteroom should operate at a positive pressure
relative to the processing area but negative or lower pressure relative
to the outside or adjacent room.


The processing of materials for drug products shall be separated from

the production of non-drug products.


Separate space for:


Cleaning mobile equipment

Storage of cleaning materials

Locker/gowning room shall be directly connected to but separated

from processing areas.

2.1.10 Toilets should not be opened directly to production areas and shall
have adequate supply of water and ventilation.

2.1.11 Experimental animals shall be housed in a separate building.[Refer to

Annex on Biological Products for further details on Animal Quarantine
and Care]

2.1.12 Defined areas for the following operations are required:

gowning/change rooms for all personnel

receiving of starting materials

incoming goods quarantine

sampling room for sampling of deliveries of starting


Page 14 of 92

storage for approved materials (chemical & packaging)

storage of reject materials


weighing / dispensing of materials

processing operations equipment washing storage of cleaned, idle/non-functional equipment major repair and maintenance activities storage of cleaning tools and supplies staging/storage of bulk products packaging / labeling operations quarantine storage for finished products storage for approved of finished products and distribution center cafeteria process water treatment
2.1.13 Interior surfaces (walls, floors and ceilings) shall be smooth, free from
cracks and open joints, shall not retain or shed particulate matter, shall
permit easy cleaning and disinfecting. The floor in processing areas
shall be made of impervious materials, laid to an even surface, shall
allow prompt and efficient removal of any spillage. Walls shall be of
impervious and washable surface. The coving of junctions between
walls, floors and ceilings in critical areas is necessary.

2.1.14 Drains shall be of adequate size with trapped gullies. Open channels
shall be avoided where possible, but if required, they shall be shallow
enough to facilitate cleaning and disinfecting.

2.1.15 Air intakes and exhausts, and associated pipework and ducting shall
be installed in a way that will avoid product contamination.

2.1.16 Production areas shall be effectively lit and ventilated with air control
facilities (including temperature, humidity and filtration), appropriate
both to the products handled, to the operation undertaken within them
and to the external environment. [refer to section 2.1.5, 2.1.6]

Page 15 of 92

2.1.17 Pipework, light fittings, ventilation points and other services in

production areas shall be installed in a way that will have cleanable
recesses and preferably located outside the processing areas.

2.1.18 Avoid having exposed overhead roof joints, pipes and ducts.
2.1.19 Electrical power supply shall be adequate to ensure the proper
functioning of production equipment and laboratory instruments.

2.1.20 The condition of buildings shall be reviewed regularly, and repaired

where necessary. Special care shall be exercised to ensure that
building repair or maintenance operations do not adversely affect

2.1.21 Storage areas shall be of adequate space, provided with suitable

lighting, arranged and equipped to allow dry, clean and orderly
placement of stored materials and products.

Special and secured areas shall be available for storage

of flammable and explosive substances, highly toxic
substances, narcotics and other dangerous drugs.

Storage areas shall be laid-out to permit effective and

orderly segregation of the various categories of materials
stored to allow FIFO system.

Segregated storage shall be provided for rejected,

recalled or returned goods.

Storage arrangements shall permit separation of

different labels, as well as other printed materials to
avoid mix-up.

Materials require special storage conditions such as

temperature and/or humidity controls. These conditions
should be monitored and records of the monitoring

2.1.22 Doors that lead from production areas directly to the outside, e.g. fire
exits, shall be secured against contamination.

Section 3


Equipment used in the manufacturing of drug products shall be of appropriate design and
construction, adequate size and suitably located in order to assure product quality and process
reproducibility and to facilitate its cleaning and maintenance.


Design and Construction

The design and construction of equipment shall fulfill the following


the equipment surfaces coming in contact with any raw material,

intermediate, bulk or finished product shall not be reactive, additive or

Page 16 of 92

absorptive so as to alter safety, strength, identity, quality or purity of

the drug beyond the established limits


equipment shall not adversely affect the product through leaking

valves, lubricant drips, inappropriate repairs, maintenance,
modifications or adaptations


materials required for specific operations, such as lubricants or

coolants shall not come into contact with any in-process materials as
to alter the strength, safety, identity, quality, or purity of raw material,
intermediate, bulk or the finished product beyond the established limits


equipment shall be easily and conveniently cleanable


all equipment designated for use with flammable substances or

chemicals shall be explosion proof


equipment employed for weighing, measuring, testing and recording

shall be regularly checked for accuracy and calibrated according to an
appropriate program and procedure; and records shall be maintained.
Calibration conducted shall be traceable to a primary standard of
calibration of an appropriate national government agency and other
reliable agency. Records of
calibration shall be provided and

3.1.7 filters for liquid filtration used in the processing of products shall not
release fibers or substances into such products.


Installation and Location


Equipment shall be suitably installed and located to eliminate crosscontamination.

3.2.2 Equipment shall be located at a sufficient distance from other

equipment to avoid congestion and to ensure that products do not
become admixed or confused with one another.

3.2.3 All open mechanical belts and pulleys shall be equipped with safety
guards. Water, steam and pressure or vacuum lines shall be installed
so as to be easily accessible during all phases of operation. These
shall be adequately labeled and marked to be easily recognized.


Each piece of equipment shall be clearly marked with an identifying

number. This number will be used on all batch directions to designate
the particular unit or apparatus used in that specific batch.


All pipes, tanks, jackets for steam or coolant shall be properly

insulated to prevent possible injury and to minimize energy loss.


Piping to equipment designated for use with the pressurized steam

shall be properly trapped and drained.

Page 17 of 92



Heating, ventilation, air conditioning, potable water, purified water,

distilled water, clean steam, compressed air, gases and other support
systems must undergo validation.


3.3.1 Equipment shall be subjected to regular maintenance checks at

appropriate intervals to prevent malfunctions or contamination that can
alter the strength, safety, identity, quality, or purity of the product
beyond established limits.

3.3.2 Written procedures shall be established and followed for maintenance

of equipment.
The preventive maintenance program shall be
structured to assure:


all equipment

the preventive maintenance schedule allocates priorities

for maintenance

the frequency for preventive maintenance for each

equipment is identified

the maintenance records are kept

that a preventive maintenance activity for critical pieces of

equipment exceeds the scheduled time interval for that
activity, quality assurance is advised of the deviation in the
maintenance schedule.


preventive maintenance is


A written record of major equipment maintenance and use shall be

included in individual equipment logs which also identifies the date,
time, product, strength and batch or lot number of each batch
processed. For equipment used solely for one product the record can
be included in the production batch records.


A comprehensive program shall cover equipment calibration. Records

shall be maintained and to highlight trends and/or exceptional reports.




Validation shall be conducted following a Validation Protocol.

Equipment validation involves three distinct stages:

Installation Qualification

Operational Qualification

Performance Qualification/Product Valida(sometimes referred as process validation)


There are a number of basic principles related to validation of new

equipment. The detail and scope of an installation and operational

Page 18 of 92

qualification exercises is related to the complexity of the equipment

involved and the critical nature of that equipment with respect to the
quality of the final product. Nonetheless, basic principles shall be
adhered to whether it is the installation and operation of a simple
weighing balance or an autoclave. These basic principles are:

Section 4

Install the equipment in accord with an installation plan per

supplier's manual or by any special purchase

The requirements for calibration, maintenance and

cleaning are developed first as draft procedures, reviewed
and finally issued as authorized standard operating
procedures (SOP) and become part of the SOP program
of the company.

Establish operating requirements and conduct test to

assure equipment is operating correctly, under normal and
worst case conditions.

Finalize and document operator-training requirements

pertaining to new equipment.


High level of sanitation shall be practiced in every aspect of manufacturing drug products. The
scope of the sanitation and hygiene program covers personnel, premises, equipment and
apparatus, production materials and containers and anything that could become a source of
contamination to the product. Potential sources of contamination shall be eliminated through an
integrated comprehensive program of sanitation and hygiene. In all instances, the sanitation and
the hygiene procedures should be validated and periodically assessed to ensure that the
effectiveness of the operation meets the requirements.




All personnel, prior to and during employment, shall undergo health

examinations. Operators required to undertake visual inspections shall
also undergo periodic eye examination.


Personal hygiene shall be observed by all those concerned with the

manufacturing processes.


Any person shown at any time to have an apparent illness or open

lesions that may adversely affect the quality of products shall not be
allowed to handle raw materials, packaging materials, in-process
materials, and drug products until fit to work.


All employees shall be instructed and encouraged to report to their

immediate supervisor any health condition that may adversely affect
the product.

Page 19 of 92


Direct contact shall be avoided between the operator and raw

materials, intermediate or bulk products.


Personnel engaged in the manufacturing of drug products shall wear

clean clothing appropriate for the duties they perform. Soiled uniforms
shall not be used and be stored in closed containers until properly
laundered or disposed.


Only authorized personnel shall enter those areas of the buildings and
facilities designated as limited-access areas.


Personnel shall be instructed to wash their hands before entering

production areas. Signs to this effect shall be posted.


Smoking, eating, drinking, chewing and other activities; keeping plant,

food, drink, smoking material and personal medicines shall be
restricted to specific areas and not permitted in production, laboratory,
storage areas and other areas where they might adversely affect
product quality.

4.1.10 Personal hygiene procedures including requirement of using protective

clothing shall apply to all persons entering production areas, whether
they are temporary or full-time employees or non-employees on
company property, e.g. contractors employees, visitors, senior
management and inspectors.


Premises used for manufacturing drug products shall be suitably constructed to
facilitate good sanitation.



Adequate, well-maintained, and properly sited facilities shall be



Suitable locker facilities shall be provided in appropriate locations.


The preparation, storage and consumption of food and beverages

shall be restricted to cafeteria/lounge. These facilities shall meet
sanitary standards.


Waste materials shall not be allowed to accumulate. It shall be

collected in suitable receptacles for removal to collection points
outside the buildings and should be disposed off properly in a safe
sanitary manner at regular and adequate intervals.


Rodenticides, insecticides, fumigating agents and sanitizing materials

used within the premises shall not be permitted to contaminate
equipment, raw and packaging materials, in-process materials or
finished products.



Equipment shall be cleaned according to established procedures

immediately after use and shall be kept or stored in a clean condition

Page 20 of 92

and be checked for cleanliness prior to each use to ensure that all
products or materials from the previous batch has been removed.

Section 5


Vacuum or wets cleaning methods are to be preferred. Compressed

air and brushes shall be used with care and avoided if possible, as
they increase the risk of product contamination.


Cleaning and storing of mobile equipment and storing of cleaning

materials shall be done in rooms separated from processing areas.


Written procedures in sufficient detail shall be established and

followed for cleaning and sanitizing equipment, and containers used in
the manufacture of drug products. These procedures shall be
designed to prevent equipment contamination by cleaning or sanitizing
agents and shall include responsibility for cleaning schedule, method,
equipment and materials used in cleaning operations, the method of
disassembling and reassembling equipment as appropriate to assure
proper cleaning and sterilization, removal of previous batch
identification, protection of clean equipment from contamination prior
to use.


Records of cleaning, sanitizing, sterilization and inspection prior to use

shall be maintained.


Weighing and measuring equipment shall be calibrated regularly for

accuracy and precision.




Materials shall be stored in an orderly manner to prevent any risk of mix-up or

contamination and to facilitate inspection and maintenance. Materials shall be
stored off the floor and sufficiently spaced.


The materials shall be stored under suitable environmental condition.

special storage condition shall be provided and conditions monitored.


Outdoor storage is permissible for materials in secured containers (e.g. metal

drums) and whose condition will not be adversely affected by exposure to
temperature or other conditions.


Storage operations shall be adequately segregated from other operations.

Storage operations shall be adequately segregated from other operations.


All deliveries to storage areas, including returns, shall be properly documented.

Each batch of starting and packaging materials, intermediates, bulk products
and finished products in storage areas shall have an inventory system.
Inventory system shall be periodically reconciled and if there is any discrepancy
found it shall be verified and justified when the quantity approved for use is
different from the original receipt or delivery. This shall be documented with a
written explanation.

Page 21 of 92



Raw materials and packaging materials shall be returned to storage areas

following clearly defined operating procedures.


All raw materials, packaging materials, intermediate and bulk products returned
to storage areas shall be properly documented and reconciled.


All raw materials and packaging materials delivered shall be checked

for proper identity, condition of container and approval of quality
control unit.


Rejected raw materials and packaging materials shall not be stored

together with approved materials. They are to be stored in the
assigned location for rejects.


Printed packaging materials shall be stored in a restrictive storage

area and dispensed under strict supervision.


The First Expiry First Out system (FEFO) on approved raw materials
shall be used.


Raw materials shall be re-tested for identity, strength, quality and

purity as necessary e.g. after storage periods, or after exposure to air,
heat or other conditions that may adversely affect their quality.


There shall be a written procedure or system on re- evaluation of

residual raw and packaging materials before use.


All incoming, outgoing and remaining materials shall be recorded. The

record shall contain information on suppliers, batch or lot number,
quantity and number of containers, control number, date of receipt or
issuance, date of release and date of expiry if any.


Each batch of starting materials delivered shall have assigned

reference number or control number that will identify the delivery or
batch throughout storage and processing. This number shall appear
on the labels of the containers and permit access to records where full
details of the delivery or batch to be checked. Different batches within
one delivery shall be regarded as separate batches for sampling,
testing and release purposes.


Each starting material employed prior to release for use shall be in

compliance with its material specification and be labeled with the
name designated in the specification. Unauthorized abbreviations,
codes or names shall not be used.

5.7.10 Each delivery shall be visually checked on receipt for general

condition, integrity of container(s), spillage and possible deterioration,
and be sampled by personnel and methods of sampling approved by
the quality control manager. The sample shall be regarded as
separate batches for sampling, testing and release purposes.

5.7.11 Steps shall be taken to provide assurance that all containers in a

delivery contain the correct starting materials, and to safeguard

Page 22 of 92

against mislabeling of the containers by the supplier. A listing of

standard names of chemical materials shall be available for reference.

5.7.12 Deliveries of starting materials shall be held in quarantine until

approved and released for use on the authority of the quality control
manager or his/her designate.

5.7.13 Labels indicating status shall only be attached to starting materials by

persons authorized by the quality control. Such labels shall be of a
nature or form which prevents confusion with any similar labels
previously used by the material supplier ( e.g. they shall bear the
company name or logo). As the status of the material changes, the
status-labels shall be changed accordingly.

5.7.14 Stocks of starting materials shall be inspected at intervals to ensure

that the containers are properly closed and labeled, and in good
condition. These shall be re-sampled and re-tested and shall be
initiated by the application of retest labels and/or by similarly effective
documentary systems.

5.7.15 Starting materials, particularly those that may deteriorate on exposure

to heat shall be stored in a strictly controlled temperature room.

5.7.16 Only an authorized person using an approved procedure shall issue

starting materials. Stock record shall be maintained so that stock
reconciliation can be made or equivalent.

5.7.17 Segregated dispensing areas suitably equipped to avoid crosscontamination shall be provided. Specially equipped production areas
may be solely designated for the dispensing of sensitizing or highly
toxic materials such as hormones, cytotoxic agents and certain

5.7.18 All rejected starting materials shall be conspicuously identified, placed

separately under lock and key and shall be destroyed or returned to
the supplier as soon as possible.


Intermediate, Bulk and Finished Products


Intermediates, bulk products and finished products shall be held

pending quality control testing and disposition.


Intermediates, bulk products and finished products shall be checked to

verify that the material delivered agrees with the delivery


Each container of intermediates, bulk products and finished products

delivered to the storage area shall be checked for proper identification
and condition.


If the identity or condition of any container of intermediates, bulk

products and finished products is suspected, or does not comply with
the requirements of identity or condition, that container shall be
retained in the quarantine for quality control inspection and disposition.

Page 23 of 92

Section 6


Production shall follow defined procedures capable to provide assurance of consistently yielding
drug products that conform to their specifications.



Basic manufacturing requirements:


Equipment shall be technically suitable, well sited (so as not to

interfere with other operations), easy to clean and maintain. The
design, siting and operation of equipment shall ensure that no
contamination from foreign materials such as rust, lubricants, abraded
particles or foreign ingredients should occur.


A high standard of factory sanitation and personal hygiene is

necessary to achieve the objectives of protecting each product from
contamination by the environment or by the operations and protecting
products from cross contamination with other products. Emphasis in
this important areas shall be placed on written programs to ensure that
the steps have been logically thought out and validated.


The manufacturer shall clearly define its system of information and

control. The documentation system shall: provide unambiguous
sections to be followed, provide confirmation of performance, allow
calculation to be checked and to allow the accountability and
traceability of operators, materials and batch disposition.


Manufacturing facilities and methods shall be designed to prevent



There shall be sufficient space provided to minimize clutter and untidy

work practices to assure orderly material receivals, warehousing and
processing activities. The layout of rooms, corridors and areas, shall
provide for logical movement of materials and personnel with minimal
traffic and for operations to be carried out in defined areas.

Process Validation
A company should only use validated manufacturing processes. All established
processes, materials or products, procedures, activities, systems, equipment or
mechanism used in manufacture or control procedures may be validated
utilizing a retrospective approach.


All production procedures shall be properly validated, validation shall

be conducted in accordance with previously defined procedures and a
record of the results shall be maintained. The extent and degree of
validation depend on the nature and the complexity of the product and


The validation program and documentation shall provide evidence of

the suitability of materials, the performance and reliability of equipment
and systems and the competency of personnel.


When any master processing procedure is adopted, steps shall be

taken to demonstrate that it is suitable for routine operation and that

Page 24 of 92

the defined process, using materials and equipment specified, will

consistently yield a product of the required quality.



Significant changes in process, equipment or materials shall be

accompanied by further validation steps to ensure that the changes
continue to yield consistently a product of the required quality.


To ensure that processes and procedures remain capable of achieving

the intended results, these shall routinely undergo critical appraisal.

The presence in a drug product of any contaminant is unacceptable.
The air, water, personnel and all surfaces that come in contact with the product
during the manufacturing process are all potential sources of contamination.
Regular monitoring of the manufacturing environments shall be instituted to
assure that the risk of contamination is detected early and corrective actions are


Batch and Lot Numbering System

There shall be a system describing the details of the batch and/or lot
numbering set up to ensure that each batch or lot of intermediate, bulk or
finished product is identified with a specific batch or lot number.



A batch and/or lot numbering system applied to a processing state and

to the respective packaging stage shall be related to each other.


The batch and/or lot numbering system shall be defined to assure that
the same batch or lot numbers will not be repeatedly used.


Batch or lot numbers allocation shall be immediately recorded in a

logbook or any other means of recording. The record shall include
date of allocation, product identity and size of batch or lot.

Weighing and Dispensing

Only approved materials shall be permitted into the dispensary area. The
dispensary area is an area that permits a transition from dirt bulk storage
containers to clean containers for the dispensed materials intended for
manufacture. This stage is also the time when pallets constructed of plastic or
some other cleanable and impervious materials are used for storage of
dispensed materials and transport of bulk dispensed materials throughout the
manufacturing areas. The dispensary is an example of a gray area that is a
transition area from a black area (the warehouse) to a white area (the
processing area/s) where the cleanliness level or the reduction of transfer of
contaminants is achieved by a simple operation. Another example is operator
change and wash procedures.

6.5.1 The methods for handling, weighing, counting and dispensing raw
materials, packaging materials, intermediate products, and bulk
products shall be included in written procedures.

Page 25 of 92

6.5.2 All issuance of raw materials, packaging materials, intermediate

products, and bulk products including those for additional materials for
production orders already dispensed shall be properly documented.

6.5.3 Only raw materials, packaging materials, intermediate products and

bulk products which are approved by quality control can be dispensed.


To avoid mix-up, cross-contamination, loss of identity and confusion,

only the relevant raw materials, intermediate products and bulk
products shall be within the dispensing areas. After weighing,
dispensing and labeling, the raw materials, intermediate products and
bulk products shall be transported and stored in a manner that will
preserve its integrity until further processing.


Prior to weighing and dispensing, each container of raw materials shall

be checked for proper labeling, including the approval from quality


Capacity of weighing and measuring equipment used shall be

appropriate to the amount of materials to be weighed or measured.


For any weighing or measuring operation, two persons shall

independently verify the correctness of the identity and amount of
weighed or measured materials.


Weighing and dispensing areas shall be maintained in a clean



Weighing and dispensing operations shall be carried out with clean


6.5.10 Dispensed raw materials, intermediate and bulk products shall be

rechecked for identity and accuracy and signed by the production
supervisor or equivalent prior to delivery to the production area.

6.5.11 All materials utilized in processing shall be checked for its identity and
weight against the batch record before use.
The environment of an area shall be monitored and controlled to the
degree required for the operation to be performed. Before any
processing operation begin steps shall be taken to ensure that the
work area and equipment are free from any material product or
document not required for the current operation

6.5.12 All equipment employed in processing shall be checked before use.

Equipment should be certified in writing as clean before use.

6.5.13 All operation shall be performed in accordance with the written

procedures. Any deviation shall be justified and reported.

6.5.14 Containers and closures used for materials awaiting processing, for
intermediate products and for bulk products shall be clean and of a

Page 26 of 92

nature and type which prevent contamination or deterioration of the

product or materials.

6.5.15 All containers and equipment holding intermediate products shall be

properly labeled as to identify the material and stage of processing.
Before applying the labels, all inappropriate labels or marks previously
applied shall be completely removed or crossed out.

6.5.16 All intermediate and bulk products shall be properly labeled and
quarantined until approved and released by quality control.

6.5.17 All in-process intermediate and bulk controls shall be accurately

recorded at the time of performance. All step-wise activities in the
processing operation indicated in the batch processing record shall be
signed and dated at the time of completion of the activity.

6.5.18 The actual yield of each processing step of a production batch shall be
recorded and checked against the theoretical yield.

6.5.19 In all stages of processing, particular attention shall be given to the

possibility of cross-contamination.



Dry Materials and Products


To overcome problem of dust control and cross-contamination created

in handling of dry materials and products, special attention is needed
in the design, maintenance and use of premises and equipment.
Enclosed dust collecting systems or other suitable methods shall be


Effective dust extraction systems shall be installed with discharge

points situated to avoid contamination of other products or processes.
Effective filtration or other appropriate systems shall be installed to
retain dust.


To protect the product against contamination with fragments of metal,

glass or wood, special care shall be taken. Use of glass equipment is
to be avoided. Screens, punches, sieves and dies shall be checked for
wear or breakage before and after each use.


Care shall be taken to guard against tablets or capsule that may lodge
and remain undetected in equipment, counters or bulk containers.

Mixing and Granulation


Mixing, sifting and blending equipment shall be fitted with a dust

control system.


Critical operating parameters (e.g. time, speed and temperature) for

each mixing, blending and drying operation shall be laid down in the
master production document, monitored during processing and
recorded in the batch records.

Page 27 of 92




Filter bags fitted to fluid bed dryers shall be specific to one product


Solutions or suspensions shall be freshly prepared and consumed to

minimize the risk of contamination or microbial growth.



Tablet compressing machines shall be provided with effective dust

control facilities.


There shall be a suitable physical, procedural and labeling control to

prevent mix-up for all in-process tablets.


Accurate weighing equipment shall be used for in-process monitoring

of tablet weights.


Tablets removed from a compressing cubicle or station for testing or

other purposes shall not be returned to the batch.


Rejected or discarded tablets shall be placed in containers properly

identified and the quantity shall be recorded in the batch processing


Punches and dies shall be examined before each use for wear and
tear. A record of their use shall be maintained.


6.9.1 Air supplied to coating pans for drying purposes shall be filtered and of
suitable quality.

6.9.2 Coating solutions shall be prepared in a separate cubicle within the

coating room and used immediately to prevent microbial growth. Their
preparation and use shall be documented.

6.10 Hard Capsule filling

6.10.1 Empty capsule shells should be regarded as starting materials. They
should be stored under appropriate conditions to prevent drying and
brittleness or other effects of moisture.

6.11 Liquids, Creams and Ointments

6.11.1 Liquids, creams and ointments shall use closed system of production
and transfer to protect the product from contamination.

6.11.2 Tanks, containers, pipework and pumps shall be designed and

installed so that they may be readily cleaned and sanitized. In
particular, equipment design should include a minimum of dead-legs
or sites where residues can accumulate and promote microbial

Page 28 of 92

6.11.3 High quality stainless steel is the material of choice for parts coming
into contact with product.

6.11.4 The chemical and microbiological quality of the water used shall be
specified, monitored and documented. Water shall be of potable
quality and have an acceptable microbial count before use.

6.11.5 Where pipelines are used for delivery of ingredients or supply of bulk
products, care should be taken to ensure that such systems are easy
to clean. Pipework shall be designed and installed so that it may be
readily dismantled and cleaned.

6.11.6 Measuring systems shall be verified as accurate. Where dipsticks are

used, they shall be used only with the particular vessel for which they
have been calibrated. They shall be made of suitable non-reactive,
non-absorptive material (e.g. stainless steel).

6.11.7 Care shall be taken to maintain the homogeneity of mixtures,

suspensions, etc. during filling. Mixing and filling processes should be
validated. Special care shall be taken at the beginning of a filling
process, after stoppages and at the end of the process to ensure that
homogeneity is maintained.

6.11.8 When the finished product is not immediately packaged, the maximum
period of storage and the storage conditions shall be specified and
adhered to.

Section 7


The function of the packaging operation is to subdivide and control bulk product. These
operations shall be performed under strict control designed to protect the identity, integrity and
quality of the final package.


All packaging operations shall proceed in accordance with a SOP. Details of

the operation shall be recorded on the batch packaging record.


Before a packaging operation begin, checks shall be carried out to ensure that
the work area and equipment are clean and free from any products, product
residues or documents not required for the operation.


Finished bulk product and packaging component shall be checked and verified
for their correctness against the master packaging procedure or a specific
packaging order.


Coding of Components


Labels, cartons and other components that require pre-coding with a

batch number or lot number, expiration date, or other information
specific to a given packaging order shall be strictly controlled at all
stages of the process, from the time of delivery from the warehouse
until they become parts of finished packages.

Page 29 of 92


Components for coding shall be stored in sealed containers within an

appropriate area for proper security and segregation.

7.11.1 Coding of components shall take place in an area isolated from other
packaging operations. To avoid mix-up, only one particular printed
packaging material is permitted in a single coding station at a time.
Adequate segregation shall be maintained between coding stations.



All coded materials shall be checked before transfer to packaging.


Special emphasis shall be given to the control of pre-printed

packaging materials particularly product labels. It is important that
there be rigorous control from the draft text through artwork approval,
printing, receipt and quality control, storage, verification, issue,
application to the product unit and disposal or return of surplus. Preprinted packaging materials shall be identified by a component code
number as part of the component printed text. These code numbers
shall be unique to each amendment of text. In addition to the code
numbers, there shall be a system of bar codes that is also part of the
printed text and is unique for each amendment.


All approved pre-printed packaging materials (including approved

status labels) shall be stored separately in a locked area. Access to
this area shall be restricted to authorized persons.


Pre-printed materials shall not be over-printed with a different name,

dosage form or strength of the product. Labels shall be counted on
receipt or at the time of issuance or on line. Where batch numbers
and expiry date are added to labels off-line, this operation shall be
done in a segregated, lockable area which maybe a label store. The
coding process shall be documented and preceded with an area
clearance check that follows the standard operating procedure. A
known number of each label or pre-printed packaging material shall be
issued in sealed containers for each packaging run.

Line Clearance



Immediately prior to the placement of materials on the packaging line,

a line clearance check shall be made by a designated responsible
packaging person in accordance with a written line clearance
procedure to:

verify that all materials and packaged products from the

previous packaging operation have been removed from
the packaging line and line area

check the line and immediate area for general cleanliness


verify that the equipment has been properly cleaned.

The person responsible for the line check shall initial and date the
batch packaging documentation indicating completion of that check

Page 30 of 92



All packaging and labeling materials shall be carefully checked for

identity and conformity to the description in the batch documentation


A check shall be made of the batch number and expiry imprinted on

pre-printed packaging materials at start up and regular intervals
through the packaging run. The expiry date for a product should be
calculated from the date of the final processing stage of the product
before packaging


Upon completion of the packaging run unused, un-coded labels and

pre-printed packaging materials shall be counted and held for
destruction or be returned to the store. Damaged or defaced preprinted packaging materials shall be counted or closely estimated.


A reconciliation shall be made between the issued quantities of preprinted packaging materials and the respective numbers accounted for
on product units, as samples on bulk shipper cartons and also the
number destroyed or defaced.

In-Process Control


Written in-process control procedures shall be followed. These

procedures shall describe the point of sampling, frequency of
sampling, number of samples to be taken, specifications to be
checked, and the limits of acceptability for each specification.


In addition, in-process control shall include, but not limited to, the
following general procedures :


the product fill or count shall be checked at the start of a

packaging run and

finished packages shall be checked throughout the run at

regular intervals to assure that these fully comply with the
specifications and that all components are those specified
in the master packaging procedure.

Results of in-process tests/inspection shall be recorded, and these

documents shall become a part of the batch packaging record.

Operating Practices


Risk of packaging errors can be minimized by the following means :

the use of roll-feed labels

on-line batch coding

use of electronic code readers and labels counters

labels and other printed materials designed with distinct

marks for different products and

Page 31 of 92

in addition to visual checks during the packaging run,

independent quality control checks during and at the end
of the run should be performed.


Products of similar appearance shall not be packaged in close

proximity unless there is physical segregation.


At each packaging line the name and batch of the product being
packaged shall be displayed.


Containers in which bulk product, partly packed product, or sub-batch

is stored shall be labeled or marked with an indication of product
identity, quantity, batch and status.


Containers to be filled shall be supplied to the packaging line or station

in a clean condition.


All packaging personnel shall be trained to recognize in process

control requirements and report any deviation they may detect while
performing their specific responsibilities.


Packaging areas shall be cleaned at frequent intervals throughout the

workday and at any time a spill of material occurs. Personnel
engaged in cleaning shall be trained to avoid practices that could
cause mix-up or cross-contamination.


Any printed packaging material found during clean up operation shall

be turned over to a supervisor, and be placed in a designated
container for reconciliation and destroyed at the end of a packaging


Products filled into their final containers while waiting for labeling shall
be segregated and marked so as to avoid mix-up.
This practice
should be avoided and only be instituted in exceptional circumstances.

7.7.10 Packaging equipment whose parts do not normally come in contact

with the bulk product but in which dust, debris, packaging components
or product might collect and later fall into the product or otherwise
become a contaminant or source of mix-up, shall be appropriately

7.7.11 Measures shall be taken to control the spread of dust during

packaging especially of dry products. Segregated packaging areas
are necessary for some products e.g. potent low dose or toxic
products and sensitizing agents. Compressed air shall never be used
to clean equipment within an operation packaging area where there is
danger of cross-contamination.

7.7.12 Brushes shall be restricted in use because of the contamination

hazard of hairs or bristles and/or particles held in the brushes.

7.7.13 Personnel shall place packaging components or products in

appropriate properly identified containers.

Page 32 of 92

7.7.14 Essential supplies, such as lubricants, adhesive, inks, cleaning fluids,

etc. shall be kept in containers that look completely different from any
container that is used for product packaging and shall be clearly
labeled as to their contents.


Section 8

Completion of the Packaging Operation


On the completion of the packaging operation, the last production

package shall be carefully checked to confirm that it fully agrees with
the master packaging procedure.


Only finished goods from a single packaging operation shall be placed

on a pallet. Any partial carton and the quantity contained shall be
indicated on the carton.
The removal of excess packaging
components and bulk product, after reconciliation, shall be closely
supervised to ensure that only the packaging components and bulk
product permitted to be returned to the warehouse are saved and that
these are properly identified.


A responsible person shall oversee the counting and destruction of

non-returnable packaging components and bulk product. All unused
coded materials shall be reconciled and destroyed. Quantities
destroyed shall be recorded on the batch packaging record.


A responsible person shall calculate and record the net used for all
packaging components and bulk product.


Any unexplained yield discrepancies or failure to comply with the

specifications shall be thoroughly investigated, with consideration
extended to other batches or other products which might also be


After acceptable reconciliation, the finished product shall be delivered

to the quarantine finished product area pending final release by the
quality control department.


Finished product quarantine is the last point of control before the product enters the warehouse
and becomes available for distribution to the market. Strict controls shall be exercised to ensure
that the product and its packaging records meet all specified requirements before release to the
Written procedures shall describe the transfer of finished product into the
quarantined area, storage while waiting approval, requirements that shall be
met for approval and subsequent transfer to the finished goods warehouse.
Pending release by the quality control unit, the entire packaged batch or lot
shall be held in the finished goods quarantine.
No material except samples for the quality control unit shall be dispensed from
any product lot or batch while it is being held in the finished goods quarantine

Page 33 of 92

Physical access to the products under quarantine shall be restricted, and only
those persons actually required working in the area or who have been properly
authorized to enter the area should be allowed access.
Any finished product that requires special storage conditions shall be
appropriately labeled to show the required storage conditions, and the material
shall be stored in quarantine under the specified conditions.
Final quality control release of the product shall be preceded by the satisfactory
completion of the following events :


finished products meet quality control requirements for all processing

and packaging specifications


retention by quality control of sufficient finished market containers as

retained samples for future testing; packaging and labeling meet all
require- ments as checked by quality control


the reconciliation of printed packaging components is acceptable and


marketed packages received in the finished goods quarantine area are

reconciled with the amount shown on the transfer documents.


After the quality control unit has approved a batch or a lot, the material shall be
removed from the finished goods quarantine area to the finished goods storage.
If required by BFAD, antibiotic products should not be released without BFAD


Upon receipt of the finished goods, the warehouse unit shall make entry in the
corresponding inventory card or other system for the batch received.


Control record for shipment of finished products

Section 9


A system designed to control the shipment of finished products shall

assure that the first expiry material is distributed first.


The system shall generate records from which the distribution of each
batch or lot of drug product can be readily determined to facilitate
investigation or recall if necessary.


Written procedures describing the distribution of products (drug,

devices and other products) shall be established and followed.


Quality Control is an essential part of Good Manufacturing Practices to provide assurance that
the products will be consistently of a quality appropriate to their intended use. The involvement
and commitment of all concerned at all stages are mandatory towards the achievement of this
quality objective from the start of manufacturing to the distribution of the finished product. An
independent quality control unit shall be established.

Page 34 of 92


General Provisions


A quality control system shall be developed and designed so as to

ensure that finished products contain the correct materials of
specified quality and quantity and are manufactured under proper
conditions following standard procedures, thereby they will
consistently meet the established specifications for identity,
strength, purity, quality and safety.


Quality control involves all analytical functions conducted in the

laboratory, including sampling, inspecting and testing of starting
materials, intermediate, bulk and finished products. It also includes
stability test, environmental monitoring program, validation tests,
review of batch documentation, sample retention program and
establishing and maintaining current specification of materials,
products and their test methods.


Documentation and release procedures applied by the quality

control unit shall ensure that the necessary tests are carried out,
and that the materials are not released for use, nor products
released for distribution and sale until their quality has been
determined to meet specifications.


The quality control unit shall have the following principal duties:

to establish and revise control procedures and


to prepare detailed written instructions for carrying out

each inspection, test and analysis

to establish written sampling plans and sampling


to maintain retained sample for future reference

to release or reject each batch of starting material,

intermediate, bulk or finished product

to review all documentation relating to the batch

processing, packaging and testing of each batch of
finished product before authorizing release for

to evaluate the stability of all finished products on an

on-going basis and raw materials where necessary,
and to establish instructions for the storage of
materials and products within the manufacturing plant
on the basis of their stability data

to establish expiration dates and shelf-life of raw

materials and finished products based on their stability
data and storage condition

Page 35 of 92


to evaluate and approve any reprocessing procedure

for products

to accredit those approved suppliers of raw and

packaging materials capable of and reliable for
supplying starting materials that meet the companys
established quality specifications

to take part or assist in validation program

to evaluate all complaints received or deficiencies

noted about any batch, if necessary in co-operation
with other units of the company, and to take
appropriate corrective action

to prepare secondary reference standards as specified

in the current procedure for testing and to store these
standards under proper conditions

to maintain analytical records of the tests of all

samples taken

to evaluate returned drug products and determine

whether such products could be released or
reprocessed or shall be destroyed

to participate in the self-inspection program with other

units of the company and

to recommend toll manufacturing operations after

evaluating the toll manufacturers capability to produce
products that meet the companys specified quality

Control Laboratory



Control laboratories shall be designed, equipped and

of sufficient space to suit relevant operations.

Provisions shall be made for the proper and safe

storage of waste materials awaiting disposal. Toxic
substance and inflammable materials shall be stored in
suitably designed and storage.

The laboratories shall be physically separated from the

production rooms. Biological, microbiological and
chemical laboratories shall be segregated from each
Air handling facilities for biologicals and
microbiologicals should be separate from process air
handling facilities.

Page 36 of 92



A separate room shall be provided for instruments to

protect these against electrical interference, vibration,
contact with excessive moisture and other external
factors or where there is need to isolate the instrument.

The design of the laboratory shall take into account the

suitability of construction materials, fume prevention
and ventilation. Separate air handling units shall be
installed for biological, microbiological and radioisotope

All service pipings/pipelines and devices shall be

adequately marked and special attention paid to the
provision of non-interchangeable connections or
adaptors for dangerous gases and liquids.

A safety shower and eye-bath shall be provided in

close proximity to the laboratory working area.


Each individual engaged in the supervision or conduct

of a laboratory operation shall have proper education,
training and experience or combination thereof, to
enable the individual to perform the assigned functions.
Their duties and responsibilities shall be clearly defined
in job descriptions or by other suitable means.

Personnel shall wear protective clothing and safety

equipment such as respirators or face masks, safety
glasses and acid or alkali resistant gloves appropriate
to the duties being performed.


Control laboratory equipment and instruments shall be

suitable to the testing procedures undertaken.

Standard operating procedures shall be available for

each instrument and equipment

Equipment and instrument shall be serviced and

calibrated at pre-specified intervals and their records
shall be maintained. Pre-check of the instrument to
ensure its satisfactory functioning shall be conducted
daily or prior to using the instrument for performing an
analytical test.

The date of calibration, servicing and due date of the

next calibration shall be clearly displayed on the
equipment or by other appropriate means. Provisions
shall be made to indicate failure of equipment or
services to equipment. Defective equipment shall be
withdrawn from use until the defect has been rectified.

Page 37 of 92




Reagents and Culture Media

All reagents and culture media shall be recorded upon

receipt or preparation.

Reagents made up in the laboratory shall be prepared

following written procedures and appropriately labeled.
The label
indicate the concentration,
standardization factor, shelf-life, re-standardization due
date and storage conditions. The label shall be signed
and dated by the person preparing the reagent.

Both positive and negative controls shall be applied to

verify the suitability of culture media. The size of the
inoculum used in positive controls shall be appropriate
to the sensitivity required.

Reference Standards

Reference standards shall be under the responsibility

of a designated person.

Official reference standards shall be used only for the

purpose described in the appropriate monograph.
Secondary or working standards may be established
by the application of appropriate tests and checks at
regular intervals to correct deviations and to assure the
accuracy of the result.

All reference standards shall be stored and used in a

manner which will not adversely affect their quality.
The label of reference standards shall indicate the
concentration, date of manufacture, expiration date,
date the closure is first opened and storage conditions
where appropriate.

Specifications and Testing Procedures

Testing procedures shall be validated in the context of

available facilities and equipment before they are
adopted for routine testing.

Specifications and testing procedures established for

each raw material, intermediate, bulk and finished
product shall include specifications and testing
procedures for identity, purity, quality and strength.

Testing procedures shall include:

amount of sample necessary for

testing and retention for future

amount of each reagent, buffer

solution, etc., necessary for the tests

Page 38 of 92


equations for computation and

target value and tolerance allowable

for each test

Testing procedures shall include frequency for reassaying each raw material determined by considering
its stability.

All tests shall follow the instructions given in the

relevant test procedure for each material or product.
The result, especially where calculations are involved,
shall be checked by the supervisor before the material
or product is released or rejected.

A procedure should be available to describe the action

taken when an out of specification result is obtained.

Records of Analysis
Records of analysis shall include :

name and batch number of sample

name of the individual who takes the sample

methods of analysis

all data, such as weight, buret readings, volumes and

dilutions made

calculation in units of measurement and the formula of


statement of permitted tolerance

statement of compliance or non-compliance with


date and signature of the person performing the test

and the person verifying the calculations

recommendation for its disposal, signed and dated by
the authorized person

the name of supplier, total quantity and the number of

containers of material received and

total quantity and number of containers of raw material,

packaging material, intermediate, bulk or finished
product of each batch analyzed.

Page 39 of 92



Retention Samples

representative of each batch in each delivery of active
raw material shall be retained for a specified period.

representative of each batch of finished product in its
complete packaging form shall be retained for a
specified period. These finished product samples shall
be stored under conditions that simulate market
conditions as indicated on the labels.

Retained samples shall consist of at least double the

quantity necessary to perform all the required tests,
except those for sterility.

The quality control unit shall conduct the following validation:


Validation of Assay Procedures

The assay principle should be suitable for the prescribed
application. The validation of the analytical method is intended to
establish that performance characteristics such as accuracy,
precision linearity of response are satisfactory. When the assay
performance characteristics are not satisfactory, it will be necessary
to subject the assay procedure to appropriate review, design study,
revision or replacement.


Calibration of Instruments
Calibration of the instruments specified in the testing procedure
shall be conducted on a regular basis to ensure that they are
always performing satisfactorily.



The quality control unit shall provide assistance or take part in the
periodic validation tests carried out by other units, especially the
production unit to ensure that each manufactured product
consistently meets the established specifications.

Control of Starting Materials, Intermediate, Bulk and Finished Products


Each specification shall be approved and maintained by the quality
control unit. Periodic revisions of the specifications are necessary
to comply with the latest edition of the national pharmacopoeia or
other official compendia.



Page 40 of 92

Sampling is an important operation in which only a small fraction of

a batch is taken. Valid conclusions on the whole cannot be based
on tests which have been carried out on non-representative
samples. Correct sampling is thus an essential part of a system of
quality assurance.

Personnel who take samples shall receive initial and

on-going regular training in the disciplines relevant to
correct sampling. This training shall include:

sampling plans

written sampling procedures

the techniques and equipment for


the risks of cross-contamination

the precautions to be taken with

regard to unstable and/or sterile

the importance of considering the

visual appearance of materials,
containers and labels and

the importance of recording any

unexpected or unusual circumstances

Samples shall be representative of the batches of

material from which they are taken in accordance with
the approved written procedures.

The identity of a complete batch of raw materials can

normally only be ensured if individual samples are
taken from all the containers and an identity test
performed on each sample.

The quality of a batch of raw materials may be

assessed by taking and testing a representative
sample. The samples taken for identity testing could
be used for this purpose. The number of samples
taken for the preparation of a representative sample
should be determined statistically and specified in a
sampling plan. The number of individual samples
which may be blended to form a composite sample
should also be defined, taking into account the nature
of the material, knowledge of the supplier, and the
homogeneity of the composite sample.

The sampling plan for packaging materials shall take

account of a least the following: the quantity received,
the quality required, the nature of the material (e.g.
primary packaging materials and/or printed packaging

Page 41 of 92

materials), the production methods, and what is known

of the quality assurance system of the packaging
materials applied by the manufacturer based on audits.
The number of samples taken shall be determined
statistically and specified in a sampling plan.

Sampling shall be carried out so as to avoid

contamination or other adverse effects on quality.
Containers from which sample has been taken shall be
marked to show that sample has been removed from
them. Sampling instructions shall include:

the method of sampling and the

sampling plan

the equipment to be used

the amount of sample to be taken

instructions for any required subdivision of the sample

the type of sample container to be

used i.e. whether it is for aseptic
sampling or for normal sampling

any special precautions to be

observed, especially in regard to
sampling of sterile or noxious

the storage conditions and

instructions for the cleaning

storage of sampling equipment


Each sample container shall bear a label indicating:

name of sampled material

the batch or lot number reference

the number of container from which

the sample has been taken

signature of the person who takes the

sample and

the date of sampling

Sampling equipment shall be cleaned, if necessary

sterilized, before and after each used and stored
separately from other laboratory equipment

Page 42 of 92

Care shall be taken during sampling to guard against

contamination or mix-up of, or by, the material being
sampled. All sampling equipment which comes in
contact with the material shall be cleaned. Some
particularly hazardous or potent materials may require
special precautions.

Sampling plans for starting materials shall:

including new suppliers

differentiate between starting materials

that do not bear a manufacturers
batch number and those that do

differentiate between materials that

maybe expected to vary from
container to container (for example by
segregation or moisture uptake) and
those that may not

prescribe the action to be taken where

a delivery from an accredited or
approved supplier has failed

prescribe an increased sampling rate

for damaged containers or where lots
do not appear to be homogenous

specify the extent of pooling of

samples destined for chemical tests

require the sampling operator to

initially examine each sample for
evidence of deterioration, lack of
homogeneity or other visible defects


Sampling plans for in-process materials shall:

assure a representative sample of the

batch is taken for in-process tests

prescribe an increased sampling rate

where in-process materials do not
appear to be homogenous

specify the extent of pooling of

samples destined for chemical tests

require sampling operator to initially

examine each sample for evidence of
lack of homogeneity or other visible

Page 43 of 92


Test Requirements

Raw Materials
Each raw material shall be tested for conformity with
specification for identity, strength, purity and other
quality parameters.

Packaging Materials
Packaging materials shall conform to specifications,
with emphasis placed on the compatibility of the
material with the drug product it contains. The critical
and major physical defects as well as the correctness
of identity markings that may prejudice the quality of
the product shall be examined.

Intermediate and Bulk Products

To ensure batch uniformity and

integrity, in-process control shall be
conducted by testing representative
samples of intermediate and bulk
product of each batch for identity,
strength, purity and quality as

Written procedures describing sample

taking, the controls and tests or
examinations to be conducted on inprocess product of each batch shall be
established and followed. In-process
controls are intended to monitor the
product yields and validate the
processes that may be responsible for
characteristics of in-process products.

In-process specifications shall be

consistent with the finished product
specifica- tions. They shall be derived
from previous acceptable process
average and process variability
determined by the application of
suitable statistical methods where

Rejected intermediate and bulk

products shall be identified and
controlled under a quarantine system
designed to prevent their use in further
processing unless such product is

Page 44 of 92

reprocessing later on.




Quality control approval of the product

is mandatory after completion of
critical steps of production or after the
product has been stored for a long

Finished Products

For each batch of finished product

(drugs, devices and other products),
there shall be appropriate laboratory
conformance to its finished product
specifications prior to release.

Finished products failing to meet the

established specifications and any
other relevant quality criteria shall be
Reprocessing may be
reprocessed product shall meet all
specifications and other quality criteria
prior to its acceptance and release.

Re-testing of approved materials, intermediate, bulk and finished


There shall be an appropriate time limit for storage of

each starting material, intermediate, bulk and finished
product. After this period the material or product shall
be re-tested by the quality control unit for identity,
strength, purity and quality. Based on the results the
materials/products are either re-approved for use or

If a material is subject to unusual storage condition, it

shall be re-tested and approved for use by the quality
control unit prior to processing.

Environmental Control


There shall be written procedures for environmental monitoring, for

gowning, cleaning and disinfection within manufacturing areas.
These procedures shall contain target, alert and action limits for
environmental contaminants. The procedure shall include the
action/s to be taken in the event that the limit is exceeded or
particular indicator organisms are isolated.


Regular monitoring of the process water, including at the point of

use, for chemical and microbiological quality. The sample size and
test method employed shall be capable of detecting the presence of
low levels of indicator organisms, e.g. Pseudomonas.

Page 45 of 92



Periodic microbiological monitoring of the production environment.

There are varieties of sampling techniques that are available for
monitoring of microbial contamination. Each technique has its own
value and is necessary to use a combination of techniques utilizing
a formal sampling program to identify trends or highlight exceptional
results within the manufacturing environment. These techniques

Air sampling

Settle plates

Particle counting

Contact plates

Hand plates

Water sampling


Periodic testing of the environment around the production areas for

the presence of other drug product that will contaminate the product
being processed.


Control of airborne contaminants.

In-Process Control
In-process quality control tests that maybe performed for the following (where
appropriate) by suitably trained process operators are:



Tablet granulation manufacture

moisture test

sieve (screen) analysis

Compression or encapsulation process

individual weight determination

average unit weight determination

disintegration test

friability test (compressed tablets only)

hardness test (compressed tablets only)

maintenance of x & r charts

thickness (compressed tablets only)

Page 46 of 92






Tablet coating

average unit weight

individual weight

color and coating finish

Liquid processing

clarity at final filtration


specific gravity

final batch volume

Creams, ointments, semi-solids, liniments

active material dispersion/solubilization

pH (excluding ointments)


Filling/Packaging Operations

encoded batch number and expiry date

count or measures in finished pack

label appearance and adhesion

bulk material identification

cap torque

seal integrity of strip or blister pack

correctness of first and last packages

Packaging Control


The quality control unit shall verify line clearance before the
packaging operation may proceed.


During the packaging run the in-process control inspector will collect
samples of packed unit at the beginning, middle and end of

Page 47 of 92


Packed finished products shall be quarantined until released by the

quality control unit.



Reprocessing shall not be performed without prior review and

approval of the quality control unit.


The reprocessing of a batch of product shall be considered only

after the potential risks have been formally evaluated and complied
with specifications.


The methods of reprocessing shall be specifically authorized and

fully documented. Documentation shall accurately record the
reworking processes carried out.


Additional testing of any finished product that has been reprocessed

and added shall be performed as required.


Follow-up stability study of the reprocessed product shall be

conducted as necessary.


Recovered Material


Recovered material may be reprocessed by an

appropriate and authorized method, provided that the
material was analyzed to be suitable for such

The resultant product should meet its specification and

product quality.

Documentation should accurately record the reworking

processes carried out.

Product Residues

Residues that are not suitable for reprocessing which

do not meet specifications shall not be used in
subsequent batches.

The treatment of product residues and reprocessed

material and the means of their inclusion in a
subsequent batch shall be specifically authorized and

Limits, approved by the quality control, shall be

established for the amount of any such material that
may be added to a subsequent batch.

Batches incorporating residues shall not be released

until the batches from which the residues originated
have been evaluated and found suitable for use.

Page 48 of 92



Returned Goods

A finished product returned from the manufacturers

own stores or warehouse (because, for example, of
soiled or damaged labels or outer packaging) may be
relabeled or incorporated in subsequent batches,
provided that there is no risk to product quality and the
operation is specifically authorized and documented. If
such products are re-labeled, extra care is necessary
to avoid mix-up or mislabeling.

Finished products returned from the market and which

have left the control of the manufacturer shall be
considered for re-sale, re-labeling or incorporation in a
subsequent batch only after the person responsible for
quality control has critically assessed them. The
nature of the product, any special storage condition
required, its condition and history, and the time
elapsed since it was issued shall all be taken into
account in this assessment.

Where any doubt arises over the quality of the product,

it shall not be considered suitable for re-issue for reuse.

Quality Control Evaluation on Production Procedures


The quality control unit shall participate in the development of the

master processing procedure and master packaging procedure for
each batch size of a drug product to assure uniformity from batch to
batch manufactured. Any changes and adjustments in the master
processing procedure or master packaging procedure shall have
quality control approval prior to execution in production.


The quality control unit shall approve the production equipment

cleaning and sanitation procedures.


All production and control records shall be reviewed and approved

by the quality control unit to determine the manufacturing
compliance with the established procedures before a batch of
finished product is released for distribution.


Any discrepancy or failure of a batch to meet its specifications shall

be thoroughly investigated. The investigation shall extend to other
batches of the same product and other products that may have
been associated with the specific failure or discrepancy. A written
record of the investigation shall be made and shall include the
conclusion and follow-up action.

9.10 Stability Study


A stability-testing program shall be designed to assess the stability

characteristics of drug products and to determine storage conditions
and expiration date.

Page 49 of 92



The written program shall be followed and shall include:

sample size test intervals based on statistical criteria

for each attribute examined to assure estimate of

storage conditions

reliable, meaningful and specific test method

testing of the product in the same packaging form as

that in which the product is marketed and

testing of the product for reconstitution before and after

it has been reconstituted

A stability study shall be performed under the following situations:

new products (usually performed on pilot batches)

new packages i.e. those differing from the prescribed


change in formula, processing method or source of raw


batches released by exception e.g. batches with

properties differing from standard or reworked batches

marketed products to confirm assigned shelf life


The stability data for each product unit sales pack shall be available.
The prediction of the shelf life assigned to a product pack may be
based on accelerated stability studies at elevated temperatures and
extreme conditions. These predictions of the length of shelf-life
shall at all times be conservative. Additionally, the predicted shelflife (from accelerated studies) shall be confirmed with actual shelflife studies of samples held at the storage (labeled) temperature.


The test data used to evaluate a products shelf-life

stability) shall be based on the results derived from the use of
special analytical methods that are stability indicating.


The stability profile for the products shall be verified at appropriate

intervals by supplementary testing of further batches of product.
Where applicable, the program shall include dissolution,
microbiological and preservative efficacy testing.


Records of stability data for all products shall be maintained in a

systematic tabular or equivalent format. The collected data shall be
reviewed at appropriated intervals. The assessments leading to the

Page 50 of 92

determination or amendment of shelf-life and / or storage conditions

shall be documented.


The product shelf-life program shall be documented identifying the

frequency of testing, special conditions required for each study if
applicable, the test procedure and the number of batches.


Analytical methods used for testing of samples used to determine

the stability ( shelf-life ) of drug products should be specially
designed to be a stability indicating. These methods shall by
nature of their design quantify the particular drug entity and any
breakdown products. The use of chromatographic methods is
particularly applicable in this area of testing.

9.10.10 If the stability data available for a product indicates that there maybe
a change from acceptance specifications on storage (within the
expiry date period), the specifications which each batch of that
product must meet before it is released for distribution (the release
specifications) shall have different or narrower ranges of acceptance
requirements for the variable attributes than those to which the
product must conform at anytime during its shelf-life (the expiry
specifications, or compendial monograph specifications).

9.10.11 Where this distinction is made, all relevant documents shall clearly
nominate release and expiry specifications respectively. Expiry
specifications shall be consistent with any data accepted by the
regulatory agency (BFAD) in connection with product registration
and with any compendial standards applicable to the product.

9.11 Starting Material Suppliers Rating


The quality control unit shall have joint responsibility with other
relevant departments for approving vendors who have the capability
and reliability to supply starting materials that meet established


All prospective material suppliers shall be evaluated before orders

are placed. Inspections are required where possible unless the
suppliers history, reputation or warranty negates the need for such


Inspection shall be made jointly by representatives from quality

control, production and purchasing units to determine the suppliers
suitability. As a prospective buyer, the representatives from the
quality control, production and purchasing units shall assess the
technical qualifications of the supplier and it's attitude towards


All established material suppliers should be evaluated regularly.


A list of approved suppliers of starting materials shall be established

and reviewed as necessary.

Page 51 of 92

9.12 Release for supply


Release for supply of finished product shall require the examination

and certification by Quality Control Unit or Quality Assurance that
handles and reviews the consolidated records of processing,
packaging and quality control. This is to ensure compliance with all
procedures, acceptable yields and reconciliation and compliance
with product release specifications. The checks conducted at final
release shall satisfy the following criteria:


Checks that all documentation and records are complete and free of
obvious errors, discrepancies and anomalies


A check that the yield at all critical stages in the manufacture are
satisfactory and comply with pre-determined quality assurance alert
limits for the product manufacture


A check that the accountability of pre-printed packaging materials is

satisfactory and the reconciliation between issued quantities and
used, destroyed and returned quantities is satisfactory and that any
discrepancy in the reconciliation is within a pre-determined quality
assurance alert limit


A check that the product meets its finished product release



For a sterile product a checks should be made that the sterilization

parameters for the manufacturing activities for the batch are in
accord with validation requirements for the processes
The above checks may appear as a pro-forma checklist on batch
documentation with a record of their review and certification by
quality assurance or quality control before release. Quality
Assurance is sometimes viewed as an overall management and the
allocation of duties between Quality Assurance and Quality Control
may vary considerably between manufacturers because of their
diversity both in type and size. This is acceptable provided that all
the functions are specified and carried out.

9.13 Product Complaints


A system for handling product complaints shall be designed which

includes written procedures and indicates the responsible persons
through whom the complaints are to be channeled.


All written and oral complaints regarding a drug product shall be

thoroughly investigated. The quality control unit in conjunction with
the production or marketing unit shall investigate the cause of the
complaints and take appropriate measures to prevent their


Records of complaints and their handling shall be made and include

the following information:

Page 52 of 92


Contents of Complaints. It shall include:

name, dosage form, package form and

batch number

date, place of occurrence, name and

address of complainant and

nature of complaints in detail

Result of Investigation. It shall cover the following:

the product under complaint (its

condition, the condition of how the
product is used, etc.)

the retain sample, where necessary


production and storage
records of the product


evaluation of the Results of Investigation

follow-up measures such as remedial action for

improvement, reply to the complainant, or product

The product complaint records shall be maintained for a specified


9.14 Returned Goods

The quality control unit shall be responsible for examining products that are
returned because of complaints, damage, expiration or other circumstances that
may prejudice the quality of the products.


Returned drug products shall be identified as such and stored in a

separate secured area.


All returned products shall be critically evaluated for necessary

analysis and testing in addition to physical inspection when
condition warrants. Those products that meet the appropriate
specifications and characteristics may be transferred to a status of
finished products and returned to inventory for resale.


In case the returned product is redressed for resale, it shall be

recoded accordingly.


Any returned product which is suspected of being subjected to

improper storage conditions including extremes in temperature,
humidity, fumes, pressure or fire shall be destroyed.

Page 53 of 92


Returned products to be destroyed shall be handled in such a way

so as to assure destruction and also prevent the possibility of the
products getting into hands of unauthorized persons.


Records of returned products shall be maintained and shall include

the name, strength, dosage form, package form, batch number,
reason for the return, quantity returned, date of disposition and
method of ultimate disposition.

Documentation in any manufacturing is a part of management information system, which includes
specifications, procedures, methods and instructions, reports and records and other documents
that are required for planning, organizing, controlling and evaluating the whole activities of drug
Documentation is essential for ensuring that each personnel receives clear and detailed
description of the relevant job assignment to minimize the risk of misinterpretation and error,
which are normally associated with habits of communication by oral practice only.
A documentation system shall be designed such that a complete history of each manufactured
batch or lot of product can be traced back to enable investigation of the batch or lot whenever it
becomes necessary.
A documentation system is also required for monitoring and controlling the condition of
environment, equipment and personnel.

10.1 General Provisions


Documents shall be prepared and designed carefully for easy,

correct and effective use.


Documents shall contain records of activities within production,

quality control, equipment maintenance, warehouse, distribution and
other specific activities related to Good Manufacturing Practice.


Each document shall have the following information:

The users company or trading name

The purpose of the document and title

A document identity number which uniquely identifies

the document and indicates revision status

Date of effectivity and review, particularly in the case of

Standard Operating Procedures (SOPs)

The distribution list and where copies are distributed

Page number including the total number of pages

Page 54 of 92

Signature of the persons, who prepared, checked and

authorized the document for use and the respective
dates for these actions. In appropriate circumstances,
the person who prepared the document may also
carryout the requirements for the person who checks
the document. Master batch documents, standard
operating procedures, specifications and other
documents related to/ product quality shall be
authorized by the person responsible for the quality
assurance or that persons delegate as well as by a
production or relevant manager.


It shall be apparent from the document the way in which it shall be

used and by whom. The reason for revision and up-to-date details
shall be documented.


Documents shall contain all-important data, which shall be

reviewed, updated or amended as necessary and formally
It shall include provision for periodic review and


There shall be a system for preventing the use of superseded



Where documents while in use require entry of data or additional

information, then the format shall:

Provide sufficient space for the entry or additional


Allow adequate spacing between entries

Clearly indicate what is to be included

Entries or additional information shall be handwritten

clearly and legibly in permanent ink.


Any error made or detected on a document shall be corrected in

such a manner that the original entry is not lost. The correction is
made close to the original entry, initialed and dated.


Any document containing instructions shall be clear and precise in a

language easily understood by the user.

10.1.10 Each manufacturing document shall be dated, signed and

authorized by the production manager and quality control manager.
Departments or other persons receiving copies of the document
should be listed at least on the original copy.

10.1.11 Documents shall be readily available to all parties concerned.

Signature specimen of personnel involved in the manufacturing
plant shall also be maintained.

10.1.12 Batch related documents and records as well as reference sample

of finished drug product and starting material shall be retained for a

Page 55 of 92

period specified by the manufacturer or the relevant government


10.2 Specifications
Document of specifications shall include specifications for raw materials,
packaging materials, intermediate products, bulk products and finished


Raw Material Specifications


Specifications for raw materials shall include:

material name/code designated by

own company

material name/code designated by the


material description, physical and

chemical characteristics, and its
microbiological standards, if any

employed for testing the material

retest interval of the material in store, if


storage requirements and other safety


shelf - life of material

name of approved supplier and

date of issue

The raw material specifications are kept either

separately or attached to the master production

Packaging Material Specifications

Specifications for packaging materials shall include:

material name/code desig-nated by

own company

material name/code designated by the


Page 56 of 92

material description such as type of

material, thickness, dimension, color,
strength and printed text

technical drawing where applicable

pharmacopoeia or the method used for
testing the material

retest interval of the material in store, if


storage requirements and other safety


shelf - life of material, if any

name of approved supplier and date of issue


The packaging material specifications are kept either

separately or attached to the master production

Specifications for Intermediate Products, Bulk Products and

Finished Products

Specifications for intermediate products, bulk products

and finished products, according to its dosage form
and stage of manufacturing shall include:

product name/code

dosage form and strength of product

product description, physical and

chemical characteristics of the product
and its microbiological standard, if any

pharmacopoeia or the method used for

physical properties such as fill weight

or volume and their tolerance limits,
pH, viscosity, density, hardness,
friability, disintegration time and the
dissolution rate, if required

the finished product specification

should also specify the description of

Page 57 of 92

the product presentation including the

pack size

shelf-life of the product and

storage requirements and other safety


The specifications for intermediate product, bulk

product and finished product should be kept either
separately or attached to the master production

10.3 Production Documents


Master Batch Production Record

A master production document should include the

product name, dosage form, strength and description,
the writers name and department, name of verifier and
list of document distribution.
The master batch production record should contain the
following data:

general information des-cribing the

product and the type of packaging
material to be used or its alternative,
statement of the product stability,
safety precautions during storage and
other precautions to be taken during
processing and packaging of the

product composition or formula for one

dosage unit as well as for a sample of

a complete list of raw materials

whether they remain unchanged or
become altered during processing

reference to the specification of raw


a complete list of packaging materials

reference to the
packaging material

processing and packaging procedures

list of equipment which may be used

for processing and packaging

Page 58 of 92




in-process control during processing

and packaging and product shelf-life

Master Processing Procedure

A master processing procedure is a document from

which copies are made for use in the processing of
individual batches of product.

The master processing procedures shall outline a

complete and detailed procedure and instruction for
processing a product. It shall include the required inprocess control that shall be performed by production
and quality control staff, safety precautions and
specific conditions that shall be applied throughout the
process and during storage of intermediate and bulk
product. The master processing procedure shall
provide a blank space or form for recording the
processing data. The master processing procedure
shall be prepared, dated and signed by the production
manager, and independently checked, dated and
countersigned by the quality control manager.

The master processing procedure should include the


product name,

a complete list of raw materials,

designating the names and codes
monograph references

quantity of each active and inactive

material expressed in a metric system
unit of measurement for one dosage
unit or batch size

statement of calculated overage of a

raw material used in the process

permissible quantity of a product

residue which may be added to the
batch in process

numbers of different batches of lot of

an active or inactive raw material
which may be used in a batch of

Page 59 of 92





statement of the theoretical yield and

percentage limits of the actual yield

process location and equipment to be


Master Packaging Procedure

A master packaging procedure is a document from

which copies are made for use in the packaging of
individual batches of product.

The master packaging procedure shall outline a

complete and detail procedure and instructions for
packaging a product including the required in-process
control which shall be performed by production and
quality control staff, safety precautions and specific
conditions that shall be applied through the packaging
operation. The master packaging procedure shall
provide a blank space or form for recording the
packaging data. The master packaging procedure shall
be prepared, dated and signed by the production
manager, and independently checked, dated and
countersigned by the quality control manager.

The master packaging procedure shall include the


product name, dosage form and

strength and description of bulk

a description of containers, closures

including a specimen of the product
label and other labeling material which
are signed and dated by the
authorized person to approved such

procedure for reconciliation of the

issued quantities of bulk product and
packaging materials with the number
of unit packs produced

statement of the theoretical yield and

percentage limits of the actual yield

packaging line and equipment to be


Page 60 of 92


Batch Processing Record

For each batch of product, a batch processing record

shall be prepared. The record shall contain a complete
information of the processing and control of the batch.
The batch processing record form is reproduced from
its master processing procedure and shall be checked
for accuracy, dated and signed by the production

The batch processing record shall show that each step

of processing has been accomplished and include the
following data:

batch number

completion of processing and any
significant intermediate stages

identity of major equipment and lines

or location used

actual weight or volume and the lot or

batch number of each raw material
used in the process, and the
signatures of the persons checking
and counter-checking the dispensing
of the materials as well as processing
the batch

batch number or clearance reference

number and the quantity of any
product residue or recovered material
used in the process

in-process control and laboratory test


actual yield and its percentage against

the theoretical yield after each critical
step of processing

any sampling performed during

various steps of processing including
the quantity taken

initials of the operator and supervisor

who check each step of the process detail of any deviation from the master

processing procedure and approval for
such deviation

Page 61 of 92 signature and date of approval from an

authorized person to signify that all
steps of processing have been
performed in accordance with the
master processing procedure and any
process deviation or yield discrepancy
is adequately explained and investigation of a specific process

failure or yield discrepancy


Batch Packaging Record

For each batch of product, a batch packaging record

shall be prepared. The record shall contain a complete
information of the packaging and control of the batch.
The batch packaging record form is reproduced from
its master packaging procedure and shall be checked
for accuracy, dated and signed by the production

The batch packaging record shall show that each step

of packaging has been accomplished and contain the
following data:

Batch number

dates of starting and finishing the


identity of major equipment and lines

or location used

actual quantity and lot or batch

number of each packaging material
and bulk product used, and signatures
of the persons weighing or counting
the quantity and performing the

in-process control test and results

record of cleaning of the equipment

used for packaging

line clearance check by an authorized

person before and after use of the line

actual yield and its percentage against

the theoretical yield at the completion
of packaging

samples of packaging materials used

and their control records, including
materials that are already coded

Page 62 of 92 any

sampling performed during

various steps of processing including
the quantity taken initials of the operator and supervisor

who perform and check each step of
the packing record of reconciliation and disposition

of unused packaging materials test reports of the finished product and investigation of a specific process
failure or yield discrepancy

10.4 Quality Control Documents

The documents required in quality control are quality control procedures and
test methods. The procedure for sampling is a very important document in
quality control; and record of analysis and test report. The records of stability
test results are usually presented separately. A test report may take the form of
certificates of analysis.


Procedure for sampling

The procedure for sampling shall outline the design and method of
sampling which should be approved, signed and dated by an
authorized person. The procedure shall include the following:


method of sampling including the sampling plan and

standard used in the sampling plan

equipment and sample container to be used

precautionary measures to be taken during sampling

including use of special clothing by the person taking
the sample

name of person or unit authorized to take the sample

location of sampling

quantity of sample taken and

method sub-dividing the sample taken, if required

Test Method
The test method is a detailed procedure for sampling and testing of
starting materials, intermediate, bulk and finished products against
their specifications. The test method shall include the name of
reagent for analysis, identification test and assay of the material

Page 63 of 92

under test as well as the computation formula to obtain the

analytical result.


Record of Sampling
A record of sampling shall be prepared in accordance with the
approved procedure for sampling.


Record of Analysis and Test Report

A record of analysis and test report shall be prepared

for each lot or batch of starting material, intermediate,
bulk and finished product following the approved
method of testing. The record of analysis and test
report shall include the statement of release or
rejection of the material or product, the date and
signatures of the analyst and supervisor.

The record of analysis shall contain the following data:

date of testing/analysis

material name including the code

number, if any

suppliers name

date of receipt of the material or


original batch/lot number;

lot/batch number or control number

assigned by quality control

quantity received and the number of


date of sampling and the quantity


reference method of testing or the

monograph used for testing test report with date and signature of

the analyst and supervisor statement of release or rejection from

quality control with signature of the
responsible person and the date number assigned to the certificate to

release or reject the product, if any

Page 64 of 92 reference number of previously issued

certificate; if required

The certificate of analysis serves as a test report that

shall contain the following data:

name and address of the manufacturer

or organization issuing the certificate

certificate number

name, dosage form and strength of the


date of receipt of the material or


original batch/lot number;

lot/batch number or control number

assigned by quality control

quantity received

date of sampling and the quantity


reference method of testing or the

monograph used for testing test result including its tolerance limits statement of release or rejection with
explanation where necessary date and signature of the analyst,

supervisor and quality control manager number assigned to the certificate to

release or reject the product and reference number of previously issued

certificate; if required

The record of stability test shall include the

requirements outlined in No. as well as the

description of the packaging materials

used for the product

time frame of the stability study

Page 65 of 92

storage condition such as temperature

and humidity of the product under

test result of the product under study

after each time frame and

test result comparison to the product

specification and the result obtained

10.5 Warehouse and Distribution Documents

The storage and distribution of drug products shall be documented. The most
important documents in this area are inventory card and distribution record.


Inventory Card
An inventory card for each product shall be prepared. The card
contains record of the quantity received, issued and balance stock
of the starting material, intermediate product, bulk product or
finished product at any time.


The inventory card shall contain the following data:

material or product name and code


date of receipt and issuing or delivery

quantity received or issued and the

balance stock

batch number of material or product

storage location and

status of material or product, whether

under quarantine, released or rejected

It is recommended to use different colors of inventory

card for each group of product like active material,
excipient, packaging material, intermediate product,
bulk product or finished product.

The inventory card shall follow the first-in-first-out

(FIFO) principle. Deviation from this principle shall be
for a short term and only when approved by an
authorized manager.

Record of Distribution of Finished Product

The record of distribution covers distribution of finished

product. The record shall be complete, up to date and

Page 66 of 92

the progressive data of distribution can be easily

followed and retrievable to enable the manufacturer to
impose a drug recall quickly and effectively whenever it
becomes necessary.

The record of distribution shall contain the following


name and address of consignee

delivery order date and number

name, dosage form and strength of the


quantity delivered

product batch number

expiration date where applicable and

special storage requirements or

precautionary measures to handle the

The inventory of finished products shall be recorded in

an inventory card as referred to No.

10.6 Documents for Maintenance, Cleaning and Monitoring of Manufacturing

Areas and Equipment
The most important documents for maintenance, cleaning and monitoring of
manufacturing areas and equipment are the procedures and records for
maintenance and cleaning of equipment and rooms, for pest control and for
monitoring airborne particles and/or viable microorganisms in specific areas.


Procedure and Record for Maintenance and Cleaning of


A procedure for maintenance and cleaning of each

piece of equipment shall be available. This procedure
shall include the job description and the maintenance
schedule. The maintenance and cleaning of
equipment, including the repair job and replacement of
equipment parts shall be recorded.

A procedure for cleaning production equipment shall

specify cleaning of the equipment prior to change of
batch as well as change of product. The procedure
shall include the method of cleaning and the tools and
cleaning materials to be used. The cleaning operation
shall be documented and become part of the batch

Page 67 of 92


Procedure and Record for Cleaning of Manufacturing Area

A procedure of cleaning of manufacturing area shall be available.
This procedure shall include the specific area to be cleaned, the
tools and cleaning materials to be used and the time and schedule
of cleaning. The cleaning operation shall be documented.


Procedure and Record for Pest Control

A procedure for pest control shall be available. This procedure shall
include the scope and schedule of pest control, the method of
control, the tools and pesticide to be used, precautionary measures
and the persons or units involved in the pest control. The pest
control operation shall be documented.


Procedure and Record for Monitoring Airborne Particles and

A procedure for monitoring airborne particles and microorganisms in
specific areas shall be available. This procedure shall include the
method of monitoring, areas to be monitored, specifications
including alert and action levels. The result of monitoring shall be

10.7 Documents for Specific Equipment

The most important documents for specific equipment are operating and
calibrating procedure for an equipment and record of use and calibration of


Procedure for Operating a Specific Equipment

A procedure for operating specific equipment is required to prevent
mishandling of the equipment that may influence the quality of
product utilizing the equipment or cause damage to the equipment.
The procedure is normally adapted from the equipment manual.


Procedure and Record of Calibration of a Specific Equipment

A procedure for calibrating specific equipment is required to ensure
that the equipment always weighs or measures accurately. The
procedure shall include the calibration schedule, reference
standards, reagents and tools to be used and the method of
calibrating or the reference manual used for calibrating the
equipment. The calibration performed and its result shall be

10.8 Procedure and Record of Self Inspection


A procedure for self-inspecting the manufacturing facility and

system shall be available. The procedure shall include the forms to
be used and check list for self-inspection, team composition and the
schedule of inspection.

Page 68 of 92


A record of the self-inspection and its result shall be named. The

record shall contain the teams evaluation and conclusion of the
inspection and corrective actions to be taken as necessary.

10.9 Guidelines and Records of Personnel Training on Good Manufacturing




A guideline on Good Manufacturing Practices training for personnel

relevant to their duties and responsibilities shall be available.


The record shall contain the following data:

Date of training

Name of persons attending the training

Name of instructor, department or institute conducting

the training

Training materials and training ads

Demonstration provided; if any, and

Evaluation of trainee

Documents for Handling of Product Complaints, Product

Returned Products and Destruction of Products


10.10.1 Procedure and Record for Product Complaints A procedure for handling product complaints and report
of adverse reaction of product shall be available. This
procedure shall include the definition of product
complaint and adverse reaction, the type of complaint
and report, method of handling and evaluation of the
complaint and report. The records of product complaints and adverse

reaction reports shall contain the following data: product name and batch number type of complaint or report source of complaint or report sample of complaint or reported
product summary of complaint or report result of investigation

Page 69 of 92 evaluation of complaint or report and response and follow-up action to the
complaint or report

10.10.2 Procedure and Record for Returned Products A procedure for handling returned products shall be
available. The procedure shall specify the guidelines
for making decision either to salvage, reprocess or
destroy the returned product. Returned products, which
cannot be reprocessed, shall be destroyed. The
handling, disposition and follow-up actions of returned
products should be documented and reported. The procedure for handling returned products shall

include: identifying and recording the quality of

returned drug product holding the product in quarantine investigation, test and analysis of the
product by quality control critical

management decides whether the
product may be reprocessed or not additional test for a requirement of the

reprocessed product

10.10.3 Procedure and Record for Product Recall A procedure for recalling a batch or lot or all of a
finished product from market distribution shall be
available. A record of product recall shall be made and properly

documented. The record shall contain the following
data: product name, batch number and

batch size date of starting and completing the

product recall reason of recall warehouse stock and distributed stock
of the product being recalled at the
start of recall

Page 70 of 92 quantity of recall product returned from

the market source of returns evaluations of product recall follow-up actions to be taken and report on the handling of product recall
to the management and to
government authority, if required


10.10.4 Procedure and Record of Destruction of Rejected Material or

Product A procedure for destruction of rejected materials or

products shall be available. The procedure shall
include precautionary measures to prevent pollution of
the environment and actions taken to prevent misuse
of the materials or products by unauthorized persons. A record of rejected material or product destruction

shall be made. The record shall contain the following
data: product name, batch number and

quantity of rejects source of rejected material or product method of destruction and persons performing and witnessing the


The purpose of self-inspection is to evaluate the manufacturers compliance with Good
Manufacturing Practices on all aspects of production and quality control. The self-inspection
program shall be designed to detect any shortcoming towards the implementation of Good
Manufacturing Practices and to recommend the necessary corrective actions. Self-inspection
shall be performed routinely. All recommendations for corrective actions shall be implemented.
A team consisting of personnel who can evaluate the implementation of Good Manufacturing
Practices objectively shall be appointed. The procedure and record for self-inspection shall be

11.1 Items for Self Inspection

Page 71 of 92

A checklist for self-inspection shall be established to provide a minimum and

uniform standards of requirements. The list shall include questionnaires on
Good Manufacturing Practices requirements covering the following items:

11.1.1 personnel; premises including personnel facility

11.1.2 storage of starting materials and finished products
11.1.3 equipment
11.1.4 production
11.1.5 quality control
11.1.6 documentation and
11.1.7 maintenance of building and equipment
11.2 Team of Self Inspection
Management shall appoint a team of self-inspection consisting of at least three
members who are experts in their own fields and familiar with Good
Manufacturing Practices. The members of the team may be appointed from
inside or outside the company. Each member shall be independent in
performing the inspection and evaluation.

11.3 Coverage and Frequency of Self Inspection

Self-inspection may be conducted by part of unit depending on the company
requirement, however, a complete self inspection shall be conducted at least
once a year.

11.4 Self Inspection Report

A report shall be made at the completion of a self-inspection.

The report shall

11.4.1 self-inspection report

11.4.2 evaluation and conclusion and
11.4.3 recommended corrective actions
11.5 Follow - up Action
The company management shall evaluate the self-inspection report and the
corrective actions as necessary.

Page 72 of 92



12.1 Product Complaint and Report

A product complaint and report may relate to the quality, adverse reaction or
other therapeutic effect of the product. All complaints and reports shall be
thoroughly investigated and evaluated. There shall be a follow-up action after
investigation and evaluation of the complaint and report are completed.

12.1.1 A product complaint and report may be due to: a complaint about quality whether physical, chemical or
biological defect of the product or its packaging a complaint or report of adverse reaction like allergy,

toxicity, fatal or near fatal reaction and other medical
reaction and a complaint or report of the product therapeutic activity

such as the product lack of efficacy or poor clinical

12.1.2 A system for handling product complaint shall be designed and include
written procedures and indicate the responsibility of persons through
whom the complaints are to be channeled. A record shall be made for
all product complaints and reports received.

12.1.3 The relevant unit or department according to the type of complaint or

report received shall handle product complaints and reports.

12.1.4 Each complaint and report shall be thoroughly investigated and

evaluated including: a review of all information on the complaint or report an inspection or test on the complaint sample received
and if necessary on the retained sample of the same
batch and a review of all data and documentation including the batch

record, distribution record and test report of the product
complaint or report

12.1.5 Follow-up Action

A follow-up action shall be taken after investigation and evaluation of
the product complaint and report. The action may include: corrective action where applicable recall of the batch or all the finished products other appropriate action

Page 73 of 92

12.1.6 The handling of product complaints and reports including results of

their evaluation of investigation and the follow-up actions taken should
be recorded and reported to the relevant management or department
and to the government authority.

12.2 Product Recall

A product recall is a process of withdrawing one or more batches or all of a
certain product from market distribution. A product recall is instituted following
discovery of a quality defect or if there is a report of serious adverse reaction of
a product which may cause health risk. Total withdrawal of a product from
market distribution may result in a suspension or discontinuation of
manufacturing of the product.

12.2.1 Decision for Recall Decision to recall a product may be initiated by the
manufacturer or under instruction of the government
authority. Decision to recall a product shall come internally from the

quality control manager and the company management. Decision to recall may involve one or more batches or all

of the finished product. Decision to recall a product may result in suspension or

discontinuation of manufacturing of the product.

12.2.2 Institution of Recall A product recall shall be instituted immediately after
discovery of a quality defect or receiving report of adverse
reaction of the product. Products with high health risk should be prevented from

further usage by having them under embargo as well as
recalling the products immediately. The recall point shall
reach the consumer level. The manufacturer documentation system for product recall

shall ensure that recall and embargo have been adequate
quickly, effectively and completely carried out. Procedure and guideline to recall a product shall be

established to enable the recall and embargo be quickly
and effectively carried out from all points distribution. The record and report of product recall including the result
of product recall and embargo action should be properly

Page 74 of 92

12.3 Returned Product

A returned product is a finished product which is already in distribution and
returned to the manufacturer due to complaint, damage, expiration, validity or
other reasons such as the condition of the container or package which may cast
doubt on the product identity, quality, quantity and safety. The manufacturer
shall establish a procedure for holdings, investigating and analyzing the
returned product and deciding whether the product may be reprocessed or shall
be destroyed after a critical evaluation is made.
Based on the evaluation, the returned products are categorized as follows:

12.3.1 returned products which still meet their specifications and therefore
may be returned to inventory

12.3.2 returned products which may be reprocessed and

12.3.3 returned products which do not meet their specifications and cannot
be reprocessed


These guidelines do not replace any of the sections in Parts One and Two but stress specific
points for the manufacture of sterile preparations to minimize the risks of microbiological,
particulate and pyrogen contamination.
Section 1 General Characteristics

The production of sterile preparations should be carried out in clean areas,

entry to which should be through air locks for personnel and or for goods. Clean
areas should be maintained to an appropriate standard of cleanliness and
supplied with air that has passed through filters of an appropriate efficiency.


The various operations of component preparation (such as containers and

closures), product preparation, filling and sterilization should be carried out in
separate areas within the clean area.


Clean areas for the production of sterile products are classified according to the
required characteristics of the air, in grades A, B, C, and D (see Table 1).

Table 1
Maximum number of
Particles permitted per m

Maximum number
of viable microorganisms

0.5-5 m

>5 m

Permitted per m
Less than 1




Page 75 of 92


To obtain air of the required characteristics, methods specified should be used.

It should be noted that :

Laminar-airflow systems should provide a homogenous air speed of

about 0.30 m/s for vertical flow and about 0.45 m/s for horizontal
flow but precise air speeds would depend on the type of equipment.


In order to reach the B, C, and D air grades, the number of air

changes should generally be higher than 20 per hour in a room with
a good airflow pattern and appropriate HEPA (high-efficiency
particulate air) filters.


Low values for contaminants are reliable only when a large number
of air samples are taken.


The guidance given for the maximum permitted number of particles

corresponds approximately to the United States Federal Standard
209 E (1992) as follows: Class 100 (grades A & B), Class 10,000
(grade C), and Class 100,000 (grade D). It may not always be
possible to demonstrate conformity with particular air standards at
the point of fill when filling is in progress, owing to the generation of
particles or droplets from the product itself.


Each manufacturing operation requires an appropriate air cleanliness level in

order to minimize the risks of particulate or microbial contamination of the
product or materials being handled. Section 1.6 gives the minimum air grades
required for different manufacturing operations.
The particulate and
microbiological conditions given in Table 1 should be maintained in the zone
immediately surrounding the product whenever the product is exposed to the
environment. These conditions should also be achieved throughout the
background environment if no personnel are present in the processing area,
and if the standards fall for any reason it should be possible to recover the
conditions after a short " clean-up" period. The utilization of absolute-barrier
technology and automated systems to minimize human interventions in
processing areas can produce significant advantages in ensuring the sterility of
manufactured products.


Manufacturing operations are divided into three categories: first, those in which
the preparation is sealed in its final container and terminally sterilized; second,
those in which the preparation is sterilized by filtration; and third, those in which
the preparation can be sterilized either by filtration or terminally and
consequently must be produced from sterile starting materials in an aseptic
way. Area grades as specified in 1.6.1- 1.6.3, must be selected by the
manufacturer on the basis of validation runs (e.g. sterile media fills).

Terminally sterilized products: Solutions should generally be

prepared in a grade C environment in order to give low microbial
and particulate counts, suitable for immediate filtration and
sterilization. Solution preparation could be allowed in a grade D
environment if additional measures were taken to minimize
contamination, such as the use of close vessels. For parenterals,
filling should be done in a laminar-airflow workstation (grade A) in a
grade C environment. The preparation of other sterile products, e.g.
ointments, creams, suspensions, and emulsions, and filling of

Page 76 of 92

containers should generally be done in a grade C environment

before terminal sterilization.

Sterile filtered products: The handling of starting materials and the

preparation of solutions should be done in a grade C environment.
These activities could be allowed in a grade D environment if
additional measures were taken to minimize contamination, such as
the use of closed vessels prior to filtration. After sterile filtration, the
product must be handled and dispensed into containers under
aseptic conditions in a grade A or B area with a grade B or C
background respectively.


Other sterile products prepared from sterile starting materials in an

aseptic way. The handling of starting materials and all further
processing should be done in a grade A or B area with a grade B or
C background respectively.

Section 2 Personnel

Personnel required to work in clean and sterile areas should be selected with
care to ensure that they may be relied upon to observe the appropriate
disciplines and are not subject to any disease or condition which would present
any microbiological hazard to the product.


High standards of personal hygiene and cleanliness are essential. Staff should
be instructed to report any adverse health condition (e.g. diarrhea, coughs,
colds, infected skin or hair, wounds, etc.) which may cause the shedding of
abnormal numbers or type of organisms. Periodic health checks for such
conditions should be performed.


All personnel, including those concerned with maintenance employed in such

areas should receive regular training in the disciplines relevant to the correct
manufacture of sterile products, including reference to hygiene and at least the
basic elements of microbiology.

Section 3 Clothing

Personnel entering clean or sterile areas should change into special garments,
which include head, and foot wears. These garments should shed virtually no
fibres or particulate matter, and retain particles shed by the body. They should
be comfortable to wear, and loose fitting to reduce abrasion. The garments
should be restricted for use only in the relevant clean or sterile areas.


In aseptic processing area personnel should wear sterilized single or two-piece

trouser-suits, gathered at the wrists and ankles and with high necks. Headgear
should totally enclose hair and beard and be tucked into the neck of the suit.
Footwear should totally enclose the feet, and trouser-bottoms should be tucked
inside the footwear. Cleaned and sterilized protective garments should be
provided each time a person enters a sterile area. Powder-free rubber or plastic
gloves should be worn with the garment sleeves tucked inside the gloves.
Protective eye protection should be worn. A non-linting facemask should also
be comfortable to wear and discarded at least each time the sterile area is left.


Outdoor clothing should not be brought into the clean areas. Personnel entering
the changing room should already be clad in standard factory working clothes.
Changing and washing should follow a written procedure.

Page 77 of 92

Section 4


Wristwatches and jewelries should not be worn. Cosmetics should not be used.


Clean and aseptic processing area clothing should be laundered and sterilized.
Separate laundry facilities for such clothing are desirable. Washing and
sterilization operations should follow Standard Operating Procedure.

Cleanliness and Hygiene


Sterile product processing areas should be cleaned frequently and thoroughly in

accordance with a written program. Where disinfectants are used, different
types should be employed in rotation to discourage the development of resistant
strains of microorganisms. Monitoring should be regularly undertaken in order to
detect the emergence of resistant strains of microorganisms.


Disinfectants and detergents used should be monitored for microbial

contamination. Dilutions should be kept in previously cleaned containers and
should not be stored unless sterilized. Partly emptied containers should not be


Areas should be frequently monitored microbiologically by means of exposure

plates, surface sampling, air sampling or other appropriate methods. The
monitoring should be performed while normal production operations are in
progress. When aseptic operations are performed, monitoring should be
frequent to ensure that the environment is within specification. The results of
monitoring should be considered when batches are assessed for approval.

Section 5 PREMISES


The surfaces of walls, floors and ceilings should be smooth, impervious and
unbroken in order to minimize the shedding or accumulation of particulate
matter, and to permit the repeated application of cleaning agents and
disinfectants where used.


To reduce accumulation of dust and to facilitate cleaning, there should be no

uncleanable recesses and a minimum of projecting ledges, shelves, cupboards,
equipment, fixtures and fittings. Coving should be used where walls meet floors
and ceilings in sterile areas and other clean areas.


Ceilings should be adequately sealed to prevent contamination from the space

above them.


Pipes and ducts should be installed so that they do not create recesses that are
difficult to clean. They should be sealed into walls through which they pass.


Drains should be avoided wherever possible and excluded from sterile areas
unless essential. Where installed they should be fitted with effective, easily
cleanable traps and with air breaks to prevent back-flow. Any floor channels
should be open, shallow enough and easily cleanable and be connected to
drains outside the area in a manner that prevents access to microbial

Page 78 of 92


Sinks should be excluded from aseptic processing. Any sink installed in other
clean areas should be of stainless steel, without overflow, and be supplied with
water of at least potable quality.


Room temperature and humidity should be maintained at a level that will not
cause excessive sweating of operators clad in protective garments.


Access to clean and sterile areas should be restricted to authorized persons

who enter only through changing rooms where normal factory working clothes
are changed with special protective garments.


Changing rooms should be designed as airlocks and used to provide separation

of the different stages of changing, minimizing microbial and particulate
contamination of protective clothing. They should be effectively flushed with
filtered air. Hand washing facilities should be provided only in changing rooms,
not in areas where aseptic work is done.


Airlock doors should not be opened simultaneously. An interlocking system and

a visual and or audible warning system should be operated to prevent the
opening of more than one door at a time.


Conveyor belts should not pass through walls enclosing sterile areas. They
should end at the wall, products passing onwards across at stationary surface.

Section 6 Equipment

Equipment should be designed and installed so that it may be easily cleaned,

disinfected or sterilized as required.


As far as possible, equipment fittings and services should be designed and

installed so that maintenance and repair can be carried out without additional
personnel having to enter the clean or sterile areas.


Recording apparatus should be accurately calibrated on installation and

thereafter checked at scheduled intervals.


All equipment, including sterilizers, air-filtration systems, and water-treatment

systems including stills, should be subject to planned maintenance, validation
and monitoring; its approved use following maintenance work should be


A filtered air supply should maintain a positive pressure relative to surrounding

areas under all operational conditions and flush the area effectively. Moreover,
particular attention should be paid to the protection of the zone of greater risk,
that is, the immediate environment to which the product and the cleaned
components in contact with it are exposed. Decontamination facilities and the
treatment of air leaving a clean area maybe necessary for some operations.


It should be demonstrated that airflow patterns do not present a contamination

risk, for example care should be taken to ensure that airflows do not distribute
particles from a particle-generating person, operation, or machine to a zone of
higher product risk.


A warning system should be included to indicate failure in the air supply. An

indicator for pressure difference should be fitted between areas where this

Page 79 of 92

difference is important and the pressure difference should be regularly


Section 7


Consideration should be given to restricting unnecessary access to critical filling

areas, e.g. grade A filling zones, by the use of a physical barrier.


A conveyor belt should not pass through a partition between a clean area B and
a processing area of lower air cleanliness, unless the belt itself is continuously
sterilized( e.g. in a sterilizing tunnel ).


Whenever possible, equipment used for processing sterile products should be

chosen so that it can be effectively sterilized by steam or dry heat or other


When equipment maintenance is carried out within the clean area, clean
instruments and tools should be used, and the area should be cleaned and
disinfected where appropriate before processing recommences, if the required
standards of cleanliness and or asepsis have not been maintained during the
maintenance work.


Water- treatment plants should be designed, constructed, and maintained so as

to ensure the reliable production of water of an appropriate quality. They should
not be operated beyond their designed capacity. Water should be produced,
stored, and distributed in a manner that prevents microbial growth, e.g. by
constant circulation at 80 C or not more than 4 C.


The design features for facilities for manufacture of sterile products should
ensure that the areas in which product contact components are to be prepared
and which products are to be processed, filled and sealed should be segregated
from other manufacturing areas and not used for any other procedures. These
areas should be designed, operated and managed as to minimize microbial and
particulate contamination of products throughout processing. The design of
sterilizing facilities should preclude mix-up between untreated and treated
(sterilized) materials.


Cleanrooms should be effectively flushed with air supplied under positive

pressure and delivered through HEPA air filters located where the air enters the
processing environment. Air inlets should be remote from the air outlets in
order to achieve effective flushing of the room space to allow critical operations
to be located in the least contaminated stream of air. Air outlets should be at
low level.


Cleanrooms should contain the minimum of dead space, i.e. space not
effectively flushed with clean air, the minimum of obstructions to flow of clean
air, such as fittings, ledges and shelves and no extraneous equipment. The
design materials and construction should prevent access of which has not been


Cleanrooms should be provided with suitable anterooms or equivalent

separation facilities through which staff or articles may enter or leave the area.
Suitable changing and wash facilities should be provided in these anterooms.
The change areas should be arbitrarily divided into a dirty section (adjacent to
the entry to the cleanroom) to assure proper gowning procedures. A step-

Page 80 of 92

over bench should be made available to assist in change procedures and to

provide the physical division between each end of the change area.

There should be separate rooms with appropriate grade of clean filtered air for
container and closure preparation and for batch compounding.


There should be a "cascade" of air pressure values between the sterile

manufacturing area and adjacent areas. The design of the facility should assure
that all areas supplied with HEPA filtered are positive air pressure differential to
ambient air pressure and the sterile filling area is maintained at a positive
pressure differential to immediately adjacent areas. There are specific air
cleanliness requirements for different activities conducted in a cleanroom suite
of rooms.


The manufacture of aseptic fill sterile product (includes lyophilization processes)

should utilize a double barrier system. The double barrier system of
manufacture assures sterility of the finished product by filling, capping/ sealing
the sterile filtered product in a special work zone environment of class 100 air
cleanliness Air supplied by HEPA filters. The class 100 work zone (the 1
barrier) is protected by enclosing the work zone with physical barriers to assure
the laminar flow characteristics of supplied air are maintained. The work zone is
housed in a room supplied with class 10,000 air (the 2 barrier). Operators
operating in an aseptic sterile manufacturing area need to be specially gowned
in non-shedding, non-aspirating clothing to assure protection of the product and
the filling environment from microbial and particulate contamination.


The manufacture of terminally sterile products should be carried out in a class

10,000 air cleanliness environment.


Where a company is utilizing the one facility for both aseptic and terminally
sterilized product then the company should operate to the higher standard of
cleanliness at all times.


Segregated areas are required for the following operations:


depacking component from containers


equipment and component washing




filling and sealing of immediate containers


airlock or other separate area, connecting gowning and filling room


gowning room for changing into sterile working clothes prior to

entering the sterile area

Section 8 Processing
Precautions to minimize contamination should be taken during all processing
stages, including the stages before sterilization.

Preparations containing live microbiological organisms should not be made or

containers filled in areas used for the processing of other pharmaceutical
products; however, vaccines of dead organisms or of bacterial extracts maybe

Page 81 of 92

dispensed into containers, after validated inactivation and validated cleaning

procedures, in the same premises as other sterile pharmaceutical products.

The use of nutrient media that support microbial growth in trials to simulate
aseptic operations (sterile media fills," broth fills") is a valuable part of overall
validation of an aseptic process. Such trials should have the following

They should simulate as closely as possible actual operations,

taking into account such factors as complexity of operations,
number of personnel working, and length of time.


The medium or media selected should be capable of growing a wide

spectrum of microorganisms, including those that would be
expected to be found in the filling environment.


They should include a sufficient number of units of production to

give a high degree of assurance that low levels of contamination, if
present would be detected.

It is recommended that at least 3000 units of production be included in each

broth-fill trial. The target should be zero growth and anything above 0.1% of units
contaminated should be considered unacceptable. Any contamination should be
investigated. Broth fills should be repeated at regular intervals, and whenever a
significant alteration in the product premises, equipment, or process warrants

Care should be taken that validations do not harm the processes.


Water sources, water treatment equipment and treated water should be

monitored regularly for chemical, microbial and pyrogen contamination.
Records should be maintained of the results of the monitoring and of any
remedial action.


Activities in clean areas especially when aseptic operations are in progress,

should be kept to a minimum, and the movement of personnel should be
controlled and methodical, to avoid excessive shedding of particles and
organisms due to over-vigorous activity. The ambient temperature and humidity
should not be uncomfortably high because of the nature of the garments worn.


The presence of containers and materials liable to generate fibers should be

minimized in clean areas and avoided completely when aseptic work is in


The interval between the washing and drying and the sterilization of
components, bulk-product containers, and equipment, as well as between
sterilization and use, should be as short as possible and subject to a time-limit
appropriate to the validated storage conditions.


The time between the start of the preparation of a solution and its sterilization or
filtration through a bacteria-retaining filter should be as short as possible. A
maximum permissible time should be set for each product that takes into
account its composition and the prescribed method of storage.


Any gas that is used to purge a solution or blanket a product should pass
through a sterilizing filter.

Page 82 of 92

Section 9


The microbiological contamination of products (" bioburden") should be minimal

prior to sterilization. There should be a working limit on contamination
immediately before sterilization that is related to the efficiency of the method to
be used and the risk of pyrogens. All solutions, in particular large-volume
parenterals, should be passed through a microrganism-retaining filter, if
possible immediately before the filling process. Where aqueous solutions are
held in sealed vessels, any pressure-release outlets should be protected, e.g.
by hydrophobic microbial filters.


Components, bulk-product containers, equipment, and any other articles

required in a clean area where aseptic work is in progress should be sterilized
and, wherever possible, passed into the area through double- ended sterilizers
sealed into the wall. Other procedures that achieve the same end of not
introducing contamination (e.g. triple wrapping) maybe acceptable in some


The efficacy of any new processing procedures should be validated, and the
validation should be repeated at regular intervals thereafter or when any
significant change is made in the process or equipment.


Water treatment plants should be designed, constructed, and maintained to

ensure the reliable production of water of the required quality. They should not
be operated beyond their designed capacity. The water should be produced,
stored and distributed in such a manner as to discourage microbial growth.


Distilled water intended for further processing or sterilization should not stand
for more than 24 hours unless special precautions are taken, such as storage at
least at 70 C, to prevent both the growth of bacteria and the consequent
development of pyrogens.


Where water and solutions are held in sealed vessels, any pressure relief
outlets should be protected by hydrophobic microbial air filters.


When a new aseptic process is introduced, when any significant change is

made in such a process or in the equipment, when staffs are being trained and
at a regular intervals thereafter, the efficacy of aseptic procedures should be


Sterilization can be effected by moist or dry heat, by ethylene oxide, by filtration

with subsequent aseptic filling into sterile final containers, or by radiation with
ionizing radiation. Each method has its particular applications and limitations.


If biological indicators are used, strict precautions should be taken to avoid

transferring microbial contamination from them.


There should be a clear means of differentiating products that have not been
sterilized from those sterilized. Each basket, tray or other carrier of product or
component should be clearly labeled with the material name, its batch number
and an indication of whether or not it has been sterilized.


A brief summary of sterilizing parameters for each type of sterilization is as


Page 83 of 92

steam sterilization - temperature/ time/pressure


dry heat sterilization - temperature/ time





Dry heat sterilization cycles maybe modified to also meet

conditions for depyrogenation of components where


concentration/Temperature/Humidity/Pressure/ Biological indicators


Gamma Irradiation- dose of gamma rays/time


Electron beam sterilization - dose of radiation/time

Heat Sterilization

Each heat sterilization cycle should be recorded on a

temperature/time chart or by other suitable automatic means. The
time-temperature record should form part of the batch record.
Chemical or biological indicators may be used in addition, but
should not take the place of physical controls.


After the high temperature phase of a heat sterilization cycle,

precautions should be taken during cooling to prevent
contamination of a sterile load by non-sterile air entering the
sterilization unit.

Sterilization by Moist Heat


This method is suitable for water-wettable materials and aqueous

solutions. Other materials should be sterilized by other methods.


Moist heat sterilization is achieved by exposure to saturated steam

under pressure in a suitably designed chamber. In these
circumstances there is an exact relationship between the steam
temperature and pressure, but the pressure is used solely to obtain
the required temperature and otherwise contributes nothing to the
sterilization process. The time, temperature and pressure should be
used to control and monitor the process.


Items to be sterilized, other than aqueous products in sealed

containers, should be wrapped in a material which allows the
removal of air and penetration of steam, and which under normal
conditions does not permit recontamination by microorganisms after


Care should be taken to ensure that steam used for sterilization is of

suitable quality and does not contain additives at a level which could
cause contamination of product or equipment.

Sterilization by Dry Heat


Dry heat is suitable for sterilizing equipment, non-aqueous liquids

and other materials that can withstand the temperatures required.

Page 84 of 92




Heating should be carried out in an oven or other equipment that

will achieve sterilizing conditions throughout the load. Air supply and
exhaust systems to the sterilizing oven should be equipped with
suitable filters.

Sterilization by Filtration

Sterilization by filtration should not be used when sterilization by

heat is possible.


Solutions or liquids can be sterilized by filtration through a sterile

filter or nominal pore size of 0.22 micron or with at least equivalent
microorganism retaining properties, into a previously sterilized


The integrity of the filter assembly should be checked by an

appropriate method, such as bubble-point pressure test, or forward
flow pressure test immediately before and after use. Results of
these filter-integrity checks should be recorded in the batch record.


The filter should not adversely affect the solution by removal of

ingredients from it, or by release of substances into the solution.


Due to the potential additional risks of the filtration method as

compared with other sterilization processes, a second filtration using
a sterilized microorganisms retaining filter, immediately prior to
filling, is also advisable.


The period of time a sterilizing filter is in use should be limited to

ensure that there is no microbial growth in the filter.

Sterilization by Ethylene Oxide


The efficacy of ethylene oxide as a sterilant depends upon its

concentration, temperature and humidity, time of exposure and
extent of microbial contamination. Where other methods of
sterilization are possible they should be used in preference to
ethylene oxide method.


Each sterilizing cycle should be monitored with suitable biological

indictors, distributed throughout each load. The information from
these should be part of the batch record.


After exposure, materials should be held under adequate ventilation

to allow any ethylene oxide, and its reaction products to diffuse.
Care should be taken to prevent recontamination of the sterilized
goods, and a recorded check made that all biological indicators
have been removed from the load.


During each sterilization cycle records should be made of the time

taken to complete the cycle, pressure, temperature, gas
concentration and the humidity within the chamber.


The pressure, temperature and relative humidity should be

controlled and recorded throughout a cycle on a chart, or by other

Page 85 of 92

suitable automatic means. These records should be part of the

batch record.

Sterilization by Radiation

Radiation sterilization is used mainly for the sterilization of heat

sensitive materials and products. This method is permissible only
when the absence of deleterious effects on the product has been


The radiation employed may be gamma rays from a radioisotope

(e.g. Cobalt 60) or high-energy electrons (beta radiation) from an
electron accelerator.


Treatment by irradiation may be carried out by the pharmaceutical

manufacturer or by an operator of a radiation facility under contract
(a contact manufacturer), both of whom must hold an appropriate
manufacturing authorization.


The pharmaceutical manufacturer bears responsibility for the quality

of the product including the attainment of the objective of irradiation.


During the sterilization procedure the radiation dose should be

monitored. For this purpose, established dosimetry procedures
should be used, giving a quantitative measurement of the dose
received by the product itself. Biological indicators should only be
used as additional control. The information obtained should form
part of the batch record.


Care should be taken to distinguish between materials that have

been irradiated and those that have not. Design of plant and the use
of radiation-sensitive discs can ensure this.


The number of containers received irradiated and dispatched should

be reconciled with each other and with the associated
documentation. Any discrepancy should be reported and resolved.


The irradiation plant operator should certify in writing the range of

doses received by its irradiated container within a batch or delivery.


Process and control records for each irradiation batch should be

checked and signed by a nominated responsible person and should
be retained. The method and place of retention should be agreed
between the plant operator and the holder of the marketing


Microbiological monitoring is the responsibility of the pharmaceutical

manufacturer. It may include environmental monitoring where
product is manufactured and pre-irradiation monitoring of the
product as specified in the marketing authorization.

Section 10 Validation requirements for sterilization processes

Validation Studies of sterilization processes should be conducted based on documented loading
patterns for product and equipment for each different method of sterilization method employed.

Page 86 of 92


Terminally sterilized products:

10.1.1 Facilities and processing activities for preparation of product before
sterilization must assure that the bioburden of the bulk product,
contact product components and related processing equipment
used in manufacture must have low bioburden levels and this level
must be uniform throughout the batch.
10.1.2 Minimum sterilizing conditions are uniformly attained throughout the
batch and the application of the "sterilizing agent" to the batch is
also uniformly achieved.


The parameters of the sterilizing cycle are routinely monitored and

controlled for each sterilization cycle, records of this monitoring
should form part of the batch record.


All loading configurations of product, components and equipment

within the sterilizing chamber have to be standardized and
documented and the sterilization process for each load
configuration should be validated.
New (prospective) validation studies should be carried out whenever
there is a significant change in equipment, processing, loading
configuration, product or packaging.




Aseptic product manufacturing procedures, equipment and environments

should be validated for the overall performance by test runs with suitable sterile
growth media, at the initial qualification stage and at regular intervals thereafter.
In the case of liquid processing the sterile growth media should be
soybeancasein digest media and the filled containers should be incubated at
32oC + or 2oC for at least 14 days. Full microbiological media test controls
should be carried out.

For each container type filled, at least 3000 typical containers

should be subjected to the media fill exercise under normal
processing conditions but also including "worst case" situations.


Initial validation of aseptic processing should involve three media

fills, each not less than 3000 units. No growth should be observed in
the incubated units: however manufacture of products need not be
terminated if a contamination rate less than 0.1% (3 units in 3000
filled) is achieved.

For heat sterilization, whether by moist heat or dry heat, validation studies
should include the following minimum requirements:

Bioburden studies on representative samples of the filled bulk

product (before sterilization).
Heat distribution studies for each sterilizer load configuration, to
identify cold spots within the sterilizer chamber. Distribution
studies should include adequate calibrated temperature sensors to
allow the temperature profile for the chamber to be determined.
Heat penetration studies for each container size. The studies
should be designed to determine the time to bring the contents of

Page 87 of 92

the container to the prescribed sterilizing temperature.

monitors should be included in each container used: a biological
indicator and a temperature sensor.
It is important that some of the containers in this study be placed at
the cold spots of the chamber.



Determination of the Fo values (or in the case of the dry heat

sterilization Fh values) using the same number and position of the
temperature sensors as described in the heat penetration studies.

For gas (Ethylene Oxide and Ethylene Oxide plus dilution gases) sterilization
validation studies should include the following minimum requirements:

Pre-sterilization bioburden studies of representative samples of the



Temperature distribution studies on each sterilizer chamber for each

load configuration


Microbiological challenge testing used biological indicators placed in

the most difficult- sterilized site within product packs and
distributing these challenges packs throughout the load. It is
generally accepted that sufficient indicators should be used to
provide at least one indicator for 3 cubic meters of product load, but
no fewer that 10 B.I. s. This location should be documented.


Measurement of relative humidity (at least in the absence of sterilant



Studies on the efficiency of the aeration and occurrence of toxic


For gamma radiation sterilization,

following minimum requirements:

validation studies should include the

dose mapping of the radiation cycle for different product densities

10.5.2 calibration of the timers, dosimeters and spectrophotometers for

recording and monitoring validation cycles
Section 11



Water used in production of sterile products including its storage and supply
system should be controlled to assure that it would meet appropriate
specifications for each operation.


Water for injection should be produced either by distillation or other means that
will produce the same quality.


Water for injection should be stored and continuously circulated at a

temperature of at least 70 C. A recording device should be used to monitor
storage temperature. If water for injection is not circulated, it should be
discarded after 24 hours.

Page 88 of 92


Water for injection used in formulations should be controlled as a starting



Water for injection should be stored in clean, sterile, non-reactive, nonabsorptive, non-additive containers and protected from contamination.

Section 12

Filtration of Pharmaceutical Products That Cannot Be Sterilized in their

Final Container
Certain solutions and liquids that cannot be sterilized in the final container can
be filtered through a sterile filter of nominal pore size 0.22 um (or less), or with
at least equivalent micro-organism-retaining properties, into a previously
sterilized container. Such filters can remove bacteria and moulds, but not all
viruses or mycoplasmas. Consideration should be given to complementing the
filtration process with some degree of heat treatment.
Owing to the potential additional risks of the filtration method as compared with
other sterilization processes, a double filter layer or second filtration via a further
sterilized microorganism-retaining filter immediately prior to filling maybe
advisable. The final sterile filtration should be carried out as close as possible
to the filling point.
Filters that shed fibers should not be used. The use of asbestos-containing
filters should be absolutely excluded.
The integrity of the filter should be checked by an appropriate method such as a
bubble point test immediately after each use (it may also be useful to test the
filter in this way before use.) The time taken to filter a known volume of bulk
solution and the pressure difference to be used across the filter should be
determined during validation and any significant differences from this should be
noted and investigated. Results of these checks should be recorded in the
batch record.
The same filter should not be used for more than one working day unless such
use has been validated.
The filter should not affect the product by removal of ingredients from it or by
release of substances into it.

Section 13 Finishing of Sterile Products


Where detergents or similar materials are used as a pre-rinse of containers,

procedures should ensure that no residues would remain.


Containers should be rinsed at least with purified water. Personnel should not
handle containers with bare hands. Once containers have been washed, dried
and sterilized, they should be used within a specified time period.


Ampoules should be sealed by a drawing-off technique rather than by tip



The integrity of the seal of the final container should be checked by suitable

Page 89 of 92


Filled containers of parenteral products should be inspected individually. When

inspection is done visually, it should be done under suitable and controlled
conditions of illumination and background. Operators doing the inspection
should pass regular eyesight checks, with spectacles if worn, and be allowed
frequent breaks from inspection.


Where automatic, or electronic or photoelectric methods of inspection are used,

the effectiveness of the equipment should be validated and its sensitivity

Section 14 Biological and Chemical Indicators


Biological and chemical indicators used alone are not acceptable as a proof that
a sterilization process has been effective. They will show when sterilization has
failed but not necessarily prove that the process has been successful.


Biological indicators are much less reliable than physical monitoring methods,
except in ethylene oxide sterilization.


Strict precautions should be taken when handling biological indicators due to

the hazard of introducing potential contaminants into an otherwise
microbiologically clean area. They should be stored according to the indicator
of manufacturers specifications.


Chemical indicators are available for heat, ethylene oxide and radiation
sterilization, usually in the form of adhesive tapes or patches color spot cards,
small tubes or sachets. They change color as a result of chemical reaction
brought about by the sterilization process. It is possible for the change to take
place before the sterilizing time has been completed of plastic dosimeters used
in radiation sterilization.

Section 15 Quality Control --- Test requirements

15.1 Test for Sterility

Guidance on the minimum number of sample containers to be

tested and on the standard method available for testing various
types of preparations for aerobic and anaerobic bacteria, and for
fungi should be given in standard test procedure.


Samples taken for sterility testing should be representative of the

whole of the batch but should in particular include samples taken
from parts of the batch considered to be most at risk of
contamination, for example:


For products that have been filled aseptically, samples

should include containers filled at the beginning and
end of the batch and after any significant interruption of

For products that have been heat sterilized in their final

containers, consideration should be given to taking
samples from the potentially coolest part of the load.

The sterility test applied to the finished product should be regarded

only as the last in a series of control measures by which sterility is

Page 90 of 92

assured and can be interpreted only in conjunction with the

environmental and batch processing records.

Batches failing an initial sterility test should not be released on the

basis of a second test unless an investigation into the type of
organism found, and into the environmental and batch processing
records involved, show that the original test was invalid.


For injectable products, consideration should be given to monitoring

the water and the intermediate and finished product for endotoxins,
using an established pharmacopeial method that has been validated
for each type of product. For large- volume infusion solutions, such
monitoring of water or intermediates should always be done, in
addition to any tests required by the marketing authorization on the
finished product. When a sample fails a test, the cause of failure
should be investigated and remedial action taken where necessary.


Records of sterility test results should be maintained.

15.2 Test for Pyrogens



In the manufacture of any sterile product, careful consideration

should be given to the need for testing raw materials, intermediate,
bulk and finished products for pyrogens.


Water, whether as a raw material or finished product, is a particular

risk of being pyrogenic. Water for injection should be tested for
pyrogens when labelled non-pyrogenic or when filled into
containers of over 10 ml.


Pyrogens become a more serious hazard in larger volume

injections. Sterile products that have a single dose of more than 10
ml and are intravenously administered should be pyrogen free.

Sterility Test Sampling


Samples taken for sterility testing should be representative of the

finished batch and should represent the beginning, middle and end
of the batch process.
Sample size will be determined by
pharmacopeial requirements and the method of sterilization and the
controls / monitoring that was related to the sterilization process.

15.4 Sterility Test Method


The methods mainly for sterility testing are membrane filtration and
direct inoculation, however, membrane filtration is the preferred
method. All equipment used in the test method should be sterilized
by a validated sterilization procedure. All procedures related to the
sterility test procedure should be conducted under the same
conditions required for an aseptic manufacturing process i.e. a
double barrier facility with operators correctly gowned to prevent
contamination of the testing environment. Where the product to be
tested has anti-microbial activity, the membrane used should have
a hydrophobic edge to facilitate washing, to wash-out the
antimicrobial agent before introduction of media

Page 91 of 92

15.5 Sterility Test Media


The usual media are Fluid Thioglycollate medium and Soybean

Casein Digest medium. The composition of the two media are so
designed to support the growth of aerobic and anaerobic

15.6 Sterility Test Media Quality Controls


Pre-incubation period - media should be pre-incubated to establish

the sterility of the un-inoculated media. Ideally, this test should be
conducted for the same length of time as the incubation time of the
sterility test.


Fertility test - representative containers from each batch of media

should be inoculated with the low numbers (< 100 cfu) of viable
challenge microorganisms and incubated at the appropriate
temperature to demonstrate that the media will support growth.


Stasis test - at the end of the incubation period for the sterility test, a
number of containers should be inoculated with a small number ( <
100 cfu ) of challenge microorganisms. The Stasis test should be
conducted approximately three (3) times a year on validated sterility
test methods. If the test is not validated then the Stasis test should
be conducted on each sterility test.


Negative controls - are samples that have been double sterilized

that are put through the same manipulations as the test units.

All other administrative issuances or parts thereof, inconsistent with the provisions of this
Order are hereby amended, repealed and modified accordingly.
This Order shall take effect fifteen (15) days after its publication in a newspaper of
general circulation.


Secretary of Health

Page 92 of 92